Cannabinoid actions on neural stem cells: implications for pathophysiology

molecules Re iew Cannabinoid Ac ions on Neu al S em Cells: Implica ions o Pa hophysiology Rui S. Rod igues 1,2,† , Diogo M. Lou enço 1,2,† , Sa a L. Paulo 1,2 , Joana M. Ma eus 1,2 , Miguel F. Fe ei a 1,2, F ancisco M. Mou o 1,2, João B. Mo ei a 1,2 , Filipa F. Ribei o 1,2, Ana M. Sebas ião1,2 and Sa a Xapelli 1,2,* 1Ins i u o de Fa macologia e Neu ociências, Faculdade de Medicina, Uni e sidade de Lisboa, Lisboa, 1649-028 Lisboa, Po ugal; [email p o ec ed] (R.S.R.); [email p o ec ed] (D.M.L.); [email p o ec ed] (S.L.P.); [email p o ec ed] (J.M.M.); jo ge. e [email p o ec ed] (M.F.F.); [email p o ec ed] (F.M.M.); [email p o ec ed] (J.B.M.); [email p o ec ed] (F.F.R.); [email p o ec ed] (A.M.S.) 2Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa, Lisboa, 1649-028 Lisboa, Po ugal *Co espondence: [email p o ec ed]; Tel.: +351217985183 † These au ho s con ibu e equally. Recei ed: 19 Ma ch 2019; Accep ed: 3 Ap il 2019; Published: 5 Ap il 2019   Abs ac : Wi h he inc ease o li e expec ancy, neu odegene a i e diso de s a e becoming no only a heal h bu also a social bu den wo ldwide. Howe e , due o he mul i ude o pa hophysiological disease s a es, cu en ea men s ail o mee he desi ed ou comes. The e o e, he e is a need o new he apeu ic s a egies ocusing on mo e in eg a ed, pe sonalized and e ec i e app oaches. The p ospec o using neu al s em cells (NSC) as egene a i e he apies is e y p omising, howe e se e al issues s ill need o be add essed. In pa icula , he po en ial ac ions o pha macological agen s used o modula e NSC ac i i y a e highly ele an . Wi h he ongoing discussion o cannabinoid usage o medical pu poses and epo s d awing a en ion o he e ec s o cannabinoids on NSC egula ion, he e is an eno mous, and ye , unco e ed po en ial o cannabinoids as ea men op ions o se e al neu ological diso de s, speci ically when combined wi h s em cell he apy. In his manusc ip , we e iew in de ail how cannabinoids ac as po en egula o s o NSC biology and hei po en ial o modula e se e al neu ogenic ea u es in he con ex o pa hophysiology. Keywo ds: cannabinoids; neu al s em cells; neu ogenesis; egene a ion; pa hophysiology 1. In oduc ion The de elopmen o a mul icellula o ganism can be compa ed o a cho eog aphed dance o cellula and molecula in e ac ions in ol ing cell eo ganiza ion du ing p ecise s ages. Al hough in mos egions o he mammalian b ain he p oduc ion o neu ons is la gely con ined o he p ena al pe iod, in speci ic b ain egions, neu ogenesis occu s pos na ally and con inues in o adul hood. In he mammalian cen al ne ous sys em (CNS), neu al s em cells (NSCs) a e cha ac e ized by hei sel - enewal capabili y and mul ipo ency, i.e., he abili y o gi e ise o bo h neu ons and glial cells, such as oligodend ocy es and as ocy es. A “neu ogenic niche” can be de ined as a complex mic oen i onmen ha suppo s NSCs and hei p ogeny, helping o de e mine whe he NSCs emain do man o di ide, by p o iding signals ha guide ea ly s ages o p oli e a ion o di e en ia ion. One o hese signals has been shown o come h ough he ac ion o endocannabinoids (eCBs), mainly ia ac i a ion o cannabinoid ecep o s ype 1 and 2 (CB1R and CB2R). Cannabinoid esea ch has been Molecules 2019,24, 1350; doi:10.3390/molecules24071350 www.mdpi.com/jou nal/molecules Molecules 2019,24, 1350 2 o 59 cap u ing he in e es o physicians, esea che s, pha maceu ical companies and o he gene al popula ion wo ldwide because o i s b oad ange o applica ions. Impo an ly, inc easing da a has been showing an impo an ole o cannabinoids in NSC modula ion, which migh allow combining hei wide ange o ac ions wi h he mul i ude o applica ions ha s em cells o e . In his e iew, we p o ide a summa y o cannabinoid ac ions and i s e ec s in NSC modula ion bo h in de elopmen and in he adul b ain, highligh ing he ole o cannabinoids in pa hophysiology and as he apeu ic agen s o neu o egene a ion. 2. Endocannabinoid Sys em and Cannabinoids Cannabis has long been used by humans due o i s he apeu ic alue, o ec ea ional and eligious pu poses, o p oduce ood o li es ock and, o i s ibe s, o manu ac u e clo hing [ 1 ]. Nowadays, a g owing body o scien i ic e idence has been a es ing he immense po en ial o his plan o amelio a e symp oms o se e al diseases. Indeed, medical-cannabis is being used o p oposed o ea neu opa hic pain and muscle spas ici y associa ed wi h mul iple scle osis (MS), neu ode elopmen al o ms o e ac o y epilepsy, neu odegene a i e and ch onic diseases [ 1 – 10 ]. Addi ionally, he e is s ong scien i ic suppo o i s use in ea ing diso de s, o educe omi ing and nausea associa ed wi h chemo he apy, and o alle ia e human immunode iciency i us in ec ion and acqui ed immune de iciency synd ome (HIV/AIDS) ela ed weigh loss [1]. On he o he hand, ch onic consump ion o he apeu ic exposu e o cannabis can be ela ed wi h de imen al heal h e ec s. Speci ically, hea y and sus ained cannabis use is associa ed wi h cogni i e and memo y impai men s, inc eased p obabili y o de eloping schizoph enia-spec um diso de s, acu e psychosis and mania [ 11 – 15 ]. Regula cannabis abuse can esul in ch onic b onchi is and impai ed espi a o y unc ion i consumed h ough inhala ion. I can also induce physical and signi ican men al dependence, ole ance and wi hd awal symp oms [ 1 , 16 ]. The e o e, one o he challenges o cannabis esea ch is o ind ways o p e en he nega i e side-e ec s associa ed wi h cannabis-based medicines [17,18]. Acco ding o he Wo ld D ug Repo 2017, ma ijuana (d ied lea es, lowe s, s ems and seeds om he Cannabis sa i a o Cannabis indica plan s) is consumed by up o 238 million people wo ldwide, making i , by a , he mos widely used d ug [ 19 ]. The psychoac i e e ec s o cannabis consump ion include eupho ia, appe i e s imula ion, seda ion, al e ed pe cep ion, impai men s in mo o con ol and memo y de ici s [ 20 ]. These e ec s a e almos exclusi ely ela ed wi h he p esence o ∆9 - e ahyd ocannabinol ( ∆9 -THC), which was i s ly isola ed in i s pu e o m and s uc u ally desc ibed in 1964 [ 21 ]. Rega dless o i s psychoac i e e ec s, ∆9 -THC has he apeu ic alue and unique applica ions [22]. Mo e han 120 phy ocannabinoids (na u al occu ing cannabinoids) ha e now been iden i ied as cons i uen s o he cannabis plan [ 23 ]. Besides ∆9 -THC, he mos abundan cannabinoids p esen in he cannabis plan a e ∆8 - e ahyd ocannabinol ( ∆8 -THC), cannabinol (CBN), cannabidiol (CBD), cannabige ol (CBG), cannabich omene (CBC), ∆9 - e ahyd ocannabi a in (THCV), cannabi a in (CBV) and cannabidi a in (CBDV) [23]. 2.1. Endocannabinoid Sys em The endocannabinoid sys em (ECS) is a phylogene ically old modula o y sys em, ound in bo h e eb a e and in e eb a e species [ 24 – 26 ]. The ECS encompasses eCB molecules, amongs which he wo bes known and cha ac e ized a e N-a achidonoyle hanolamine (anandamide, AEA) and 2-a achidonoglyce ol (2-AG), hei syn he izing and deg ading enzymes, he wo majo cannabinoid ecep o s CB1R and CB2R, he endocannabinoid memb ane anspo e (EMT) and he CB1R in e ac ing p o ein 1a (CRIP1a) [1]. The i s iden i ied eCB was AEA [ 1 ]. B ie ly a e , wo o he eCBs we e iden i ied, namely 2-AG and 2-a achidonoyl glyce yl e he , commonly known as noladin. eCBs a e equi alen ega ding he Molecules 2019,24, 1350 3 o 59 p esence o a polyunsa u a ed a y acid moie y (such as he a achidonic acid) and a pola head g oup, composed by e hanolamine o glyce ol (Figu e 1) [27–30]. Figu e 1. Endocannabinoid signaling. (A) Endocannabinoid Re og ade Signaling and Me abolism. Molecules 2019,24, 1350 4 o 59 2-a achidonoglyce ol (2-AG) is syn hesized by wo di e en me abolic pa hways: ia he clea age o diacylglyce ol by diacylglyce ol lipase (DAGL), whe e diacylglyce ol is eleased om memb ane phospholipids by phospholipase C (PLC) o ia he ac ion o phospholipase A1 (PLA1), eleasing an sn-1 lysophospholipid om memb ane phospholipids, which is clea ed by lyso-PLC in o de o gene a e 2-AG. On he o he hand, a calcium-dependen ans-acylase (NAT) ac s on glyce ophospholipids and phospha idyle hanolamine, esul ing in N-a achidonoyl-phospha idyl e hanolamine (NA PE), which is hen clea ed by a calcium-dependen NAPE (N-acyl-phospha idyle hanolamine)-speci ic phospholipase D (NAPE-PLD), eleasing N-a achidonoyle hanolamine (anandamide, AEA) om memb ane lipids. While hyd olysis o AEA occu s pos synap ically, ia a y acid amide hyd olase (FAAH) in o a achidonic acid and e hanolamine, 2-AG is hyd olyzed by monoacylglyce ol lipase (MAGL) in o a achidonic acid and glyce ol p esynap ically. AEA and 2-AG a e usually syn hesized pos synap ically and a e eleased “on demand” o he synap ic cle , whe e hey modula e p esynap ic glu ama e gic o GABAe gic signaling by binding o CB1R o CB2R. ( B ) Non- e og ade Signaling. AEA and 2-AG signal au oc inally and non- e og adely, he pos synap ic neu on, modula ing synap ic ansmission. ( C ) Neu on-glia Signaling. Endocannabinoids p oduced by neu ons can bind o he cannabinoid ecep o s exp essed in as ocy es and mic oglia. This neu on-glia signaling is able o modula e se e al esponses. ( D ) eCB s uc u es. 2-AG and AEA ha e simila molecula s uc u es. They a e bo h pola es e lipids o med by he bond o he omega-6 a y acid a achidonic acid wi h ei he glyce ol ( o o m 2-AG) o e hanolamine ( o o m AEA). AEA is known o ac as a pa ial agonis o CB1Rs and CB2Rs, while 2-AG as a ull agonis o bo h ecep o s. AEA is syn hesized ia he ac ion o a calcium-dependen ans-acylase (NAT) on phosphoglyce ides and phospha idyle hanolamine. The esul ing N-a achidonoyl-phospha idyl e hanolamine (NA PE) is hen clea ed by a calcium-dependen NAPE (N-acyl-phospha idyle hanolamine)-speci ic phospholipase D (NAPE-PLD), eleasing he AEA om memb ane lipids. This eCB is hyd olyzed in o a achidonic acid and e hanolamine by a y acid amide hyd olase (FAAH) [ 31 ]. 2-AG, on he o he hand, can be syn hesized by wo di e en me abolic pa hways: ia he clea age o diacylglyce ol by diacylglyce ol lipase (DAGL), whe e diacylglyce ol is eleased om memb ane phospholipids by phospholipase C (PLC) o ia he ac ion o phospholipase A1 (PLA1), eleasing an sn-1 lysophospholipid om memb ane phospholipids, which is clea ed by lyso-PLC in o de o gene a e 2-AG. This eCB is hyd olyzed by monoacylglyce ol lipase (MAGL) in o a achidonic acid and glyce ol (Figu e 1A) [ 31 ]. These molecules a e no s o ed in esicles bu a he a e syn he ized and eleased “on demand,” wi h AEA being less abundan han 2-AG [1,32]. eCBs display a b oad spec um o physiologic ele an oles, pa icula ly in he CNS and pe iphe al ne ous sys em (PNS) [ 30 , 33 ]. These oles a e mainly media ed h ough he ac i a ion o CB1Rs and CB2Rs, bo h being G p o ein-coupled se en ansmemb ane domain ecep o s (GPCR) [ 33 ]. A common ea u e usually associa ed wi h CB1R and CB2R ac i a ion is he modula ion o ei he spon aneous o e oked elease o chemical messenge s, al hough his e ec is much be e cha ac e ized o CB1Rs [ 34 ]. eCBs a e p oduced and eleased om pos synap ic neu ons ei he phasically (in an ac i i y-dependen manne ), o onically (unde basal condi ions). The eleased eCBs hen ac e og adely by ac i a ing p esynap ic ecep o s (Figu e 1A) [ 33 , 35 ]. Hence, egula ion o neu o ansmi e elease cons i u es a majo physiological ole o he ECS [ 30 ]. Indeed, eCBs a e in ol ed in impo an o ms o sho and long- e m plas ici y, by supp essing neu o ansmi e elease ansien ly (sho - e m dep ession, STD) o pe sis en ly (long- e m dep ession, LTD), mainly h ough he ac i a ion o p esynap ic CB1Rs [ 33 ]. Impo an ly, eCBs can con ol bo h inhibi o y synap ic ansmission (a p ocess designa ed as depola iza ion-induced supp ession o inhibi ion, DSI) and exci a o y synap ic ansmission ( he depola iza ion-induced supp ession o exci a ion, DSE) [36,37]. A ailable e idence also sugges s ha eCB signaling can occu in a non- e og ade mode, h ough au oc ine signaling. Speci ically, eCBs can modula e synap ic ansmission h ough di ec ac i a ion o ansien ecep o po en ial anilloid ecep o ype 1 (TRPV1R), in which AEA is known o ac as a ull agonis , o ia pos synap ically loca ed CB1Rs (Figu e 1B) [38,39]. Molecules 2019,24, 1350 5 o 59 The abundancy o CB1Rs in he b ain s ongly suppo s ha his ecep o is esponsible o he majo i y o he psychoac i e e ec s o exogenous cannabinoids and o he physiological ac ions o eCBs [ 25 , 33 ]. This is u he suppo ed by he ac ha selec i e CB1R an agonis s e ec i ely abolish he psychoac i e e ec s o hese d ugs [ 40 ]. As e iewed by Solymosi and Kö al i (2017), he CB1R is abundan ly p esen in he CNS, wi h highe densi ies ound in he subs an ia nig a pa s e icula a, globus pallidus, en opeduncula nucleus, inne g anule cell laye (GCL) o he ol ac o y bulb, laye s I-III, Va and VI o he ce eb al co ex, hippocampus (pa icula ly in he molecula laye and Co nu Ammonis 3 (CA3) egion) and do sola e al s ia um; mode a e le els o CB1Rs can be ound in he hypo halamus, en al s ia um/nucleus accumbens, sep um and amygdala [1,41,42]. CB1R ac i a ion has been linked o neu op o ec ion by con olling excessi e exci a o y ansmission and calcium elease, hus p o ec ing synapses om exci o oxi y [ 43 ]. Al hough being classically iewed as a G i/o -coupled ecep o , hence ha ing mainly inhibi o y ac ions, CB1R coupling o G p o eins is mu able [ 30 , 33 , 44 ]. Indeed, CB1R is now belie ed o ha e ew “in insic” signaling p ope ies, and he ac ions media ed by i s ac i a ion a e la gely dependen on cell ype, loca ion, unc ional s a e and empo al cons ains ( o a de ailed e iew see [ 44 ]). All hese nuances can d as ically modi y he e ec s o endo-, exo- and syn he ic cannabinoids. Con a y o ini ial belie ha CB2Rs we e exclusi ely p esen in he pe iphe y, pa icula ly in he immune sys em, such as in he spleen, leukocy es and onsils, hese ecep o s we e la e iden i ied in mic oglial cells [ 33 , 45 – 48 ]. New and mo e ad anced echnological app oaches ha e allowed he iden i ica ion o CB2Rs in as ocy es and, o a la ge deg ee, in neu ons (Figu e 1C) [ 49 – 51 ]. In he CNS, hey we e i s iden i ied in b ains em neu ons and la e in inhibi o y and exci a o y neu ons in he hippocampus [ 52 , 53 ]. Nowadays, CB2Rs a e known o be exp essed in he p esynap ic e minals o gaminobu y ic acid-con aining (GABAe gic) in e neu ons in he hippocampus and medial en o hinal co ex, and in co ical and hippocampal as ocy es, whe e CB2R ac i a ion leads o highe glucose up ake [ 54 , 55 ]. CB2R le els can be inc eased in neu ons and as ocy es ollowing speci ic insul s (such as neu oin lamma ion) and also in ce ain disease s a es [ 56 – 58 ]. Addi ionally, conside ing he lack o psychoac i e e ec s ollowing CB2R modula ion, his ecep o is becoming popula as a e y p omising he apeu ic a ge [46]. When aking in o accoun he psychoac i e and he apeu ic p ope ies o cannabinoids, i is impo an o conside ha he phy ocannabinoids exis en in he cannabis plan , and in o he plan s, a ec b ain ac i i y by coupling o o he ecep o s beyond he classic CB1Rs and CB2Rs [ 1 , 23 ]. Being so, se o onin 5HT1-3A ecep o s (5HT1AR, 5HT2AR, 5HT3AR), G p o ein-coupled ecep o s 18 and 55 (GPR18, GPR55), ansien ecep o po en ial (TRP) amily, glycine ecep o s and he pe oxisome p oli e a o -ac i a ed ecep o (PPAR) assume a pa icula impo ance when conside ing he possible he apeu ic applica ions o cannabinoids [ 1 , 23 ]. Ana omical and unc ional co-localiza ion s udies ha e shown ha hese ecep o s a e exp essed in he same egions as CB1Rs and CB2Rs in he CNS and PNS [59–62]. 2.2. Cannabinoid Pha macology and Ac ions ∆9 -THC and CBD a e he wo bes known and cha ac e ized phy ocannabinoids. The ca alep ic e ec o ∆9 -THC was he i s psychoac i e e ec desc ibed o a cannabinoid [ 63 ]. This e ec is used as a s anda d o cannabinoid psychoac i i y, wi h which i has been shown o be s ongly co ela ed [ 64 ]. ∆9 -THC is known o ac as a pa ial agonis o CB1Rs and CB2Rs, p esen ing a mixed agonis -an agonis p o ile depending on he cell ype, concen a ion, ecep o exp ession and p esence o o he endo- and exo-cannabinoids ac ing as ull agonis s [ 23 , 65 , 66 ]. As e iewed by Solymosi and Kö al i (2017), ∆9 -THC can ha e di e en coupling p o iles [ 1 ]. In ac , some epo s show ha ∆9 -THC can be mo e po en on he CB2Rs and, pa adoxically, a highe concen a ions i may e en ac as an an agonis o CB1Rs [ 65 , 67 , 68 ]. ∆9 -THC is conside ed a “classic cannabinoid” because i passes he mouse e ad bioassay h ough he ac i a ion o CB1Rs, by elici ing he cannabinoid-induced e ad (hypo he mia, hypolocomo ion, ca alepsy and analgesia) [ 64 , 69 ]. As ho oughly e iewed by Solymosi Molecules 2019,24, 1350 6 o 59 and Kö al i (2017), besides i s ac ions on CB1Rs and CB2Rs, ∆9-THC binds o se e al o he ecep o s such as GPR55, as well as se o onin, opioid, glycine and PPAR γ ecep o s, which may accoun o some o he e ec s desc ibed o his phy ocannabinoid [ 1 , 23 ]. Howe e , ∆9 -THC has been shown o ha e no e ec on he TRPV1R, al hough i ac s on o he TRPV channels ( o de ailed e iews see [1,23]). CBD is a non-psychoac i e cannabinoid, he e o e, has high medicinal alue, being widely s udied. This cannabinoid has been shown o ac as an an i-in lamma o y, an ioxidan , an i-epilep ic, an i heuma ic, anxioly ic and analgesic d ug [ 1 , 23 ]. CDB was also shown o educe conges ion and nausea and o be neu op o ec i e [ 1 , 23 ]. Fu he mo e, CBD posi i ely modi ies he e ec s o ∆9 -THC by educing i s psychoac i e e ec s and by inc easing i s clinical e icacy and he du a ion o i s bene icial e ec s [ 1 , 22 ]. CBD was ea ly cha ac e ized as absen o ca alep ic e ec s, which p omp ed he now well accep ed e idence ha CBD is de oid o psychoac i e e ec s [63,64]. As e iewed by Solymosi and Kö al i (2017), CBD has low a ini y o CB1Rs and CB2Rs, exhibi ing no agonis ac i i y [ 1 , 67 , 70 ]. On he con a y, in i o s udies ha e shown ha CBD has su p isingly high po ency as an an agonis o bo h CB1Rs and CB2Rs [ 71 ]. Recen ly, howe e , i is being p oposed ha CBD may ac ually ac as a nega i e allos e ic modula o o CB1Rs [ 72 ]. Fu he mo e, i inhibi s he cellula eup ake o AEA, di ec ly a ec ing eCB one [ 23 ]. I also ac s as an agonis o GPR55 and as an an agonis o GPR18 [ 68 , 73 , 74 ]. In a ecen wo k, he an i-in lamma o y and immunosupp essi e e ec s o CBD we e p oposed o be linked wi h i s abili y o ac i a e adenosine ype 1 ecep o s [ 75 ]. CBD e ec s on TRPV, glycine, GABAAand PPARγ ecep o s we e desc ibed in de ail in [23]. eCBs, phy ocannabinoids such as ∆9 -THC and CBD, as well as o he syn he ic cannabinoids, we e shown o modula e emb yonic and pos na al neu ogenesis. In he nex sec ions o his e iew, we will u he explo e he ole o he ECS in NSC modula ion and i s implica ions o pa hophysiology. 3. Neu ogenesis 3.1. Neu ode elopmen al Neu ogenesis Du ing emb yonic de elopmen , neu ogenesis can be dis inguished in wo di e en s ages ha , al hough ha ing di e en cellula and molecula mechanisms, occu simul aneously. These a e neu ula ion and emb yonic neu ogenesis. 3.1.1. Neu ula ion A ising om he ec ode m, one o he h ee p ima y ge m laye s, he CNS begins de eloping when he neu al pla e olds in o he neu al ube, h ough a p ocess called neu ula ion, gi ing o igin o he b ain in he os al egion and he spinal co d in he caudal egion [ 76 ]. Du ing his s age he e is an inc ease in he numbe o neu oec ode m-de i ed p oli e a ing cells, expanding he neu al epi helium a di e en a es in o de o o m mo e specialized egions o he ma u e CNS [ 77 ]. These hen become he o eb ain, he midb ain and he hindb ain. Simul aneously, se e al ac o s a e eleased om he no ocho d and he somi es a ound he neu al ube, es ablishing a do so en al pola i y [ 78 ]. This pola i y is u he ein o ced by he o ma ion o he an e io -pos e io axis h ough he Wn signalling g adien (Figu e 2A) [79]. Molecules 2019,24, 1350 7 o 59 Figu e 2. Neu ogenesis. ( A ) Neu ula ion. Schema ic ep esen a ion o he neu ula ion p ocess. Neu oec ode m de i ed cells p oli e a e a di e en a es along he apicobasal pola i y. ( B ) Emb yonic Neu ogenesis. Du ing emb yonic de elopmen he cen al ne ous sys em de elops in an inside-ou ashion. Neu oepi helial s em cells, ia asymme ical di isions, di e en ia e in o adial glial cells (RGCs), es ablishing he Ven icula Zone nea he apical su ace. Nea he pial su ace, Cajal- Re zius (CRCs) cells will make he ma ginal zone du ing emb yogenesis and he co ical laye I pos na ally. The o he co ical laye s a e o med in sequen ial wa es du ing neu ogenesis. La e in de elopmen , Molecules 2019,24, 1350 8 o 59 neu al p ogeni o s en e a gliogenic mode, gene a ing as ocy es and oligodend ocy es. Neu oepi helial, adial glial and in e media e p ogeni o cells a e capable o symme ic and asymme ic di isions. ( C ) Pos na al Neu ogenesis. In he adul b ain, neu al s em cells can be ound in wo neu ogenic niches, he Sub en icula Zone (SVZ) and in he Subg anula cell laye o he Den a e Gy us (DG). In oden s ( C1 ), a e di e en ia ing in he SVZ, imma u e neu ons mig a e along he os al mig a o y s eam (RMS) o he ol ac o y bulb (OB) whe e hey will ma u e mainly in o GABAe gic in e neu ons. On he o he hand, in humans (C2), imma u e neu ons a e hough o mig a e along he RMS o he s ia um (STR). In oden s and humans, di e en ia ing neu ons om he DG ma u e by making unc ional connec ions wi h py amidal CA3 hippocampal neu ons. 3.1.2. Emb yonic Neu ogenesis Neu oepi helial p ogeni o cells (NECs) can be ound lining inside he neu al ube, which will de elop in o he en icles [ 80 ]. They o m a pseudos a i ied epi helium, as hei nuclei mig a e wi h he cell-cycle s age (in e kine ic nuclea mig a ion), being nea he apical side du ing mi osis and mo e basally du ing he S phase [ 81 ]. Like o he s em cells, NECs di ide in ei he a symme ic p oli e a i e manne , in which bo h daugh e cells emain mi o ic, o in a di e en ia i e manne , in which a leas one daugh e cell exi s he cell cycle and di e en ia es in o a mo e specialized cell [ 82 ]. This ounda ional p ocess o ms se e al laye s su ounding he lumen o he de eloping ne ous sys em, he inne -mos apical laye , whe e he p ogeni o cells eside, being he en icula zone (VZ). Radial glial cells (RGCs) a e he ea lies ype o cells o be dis inguishable wi hin he neu al epi helium. The cell bodies o hese cells can be ound in he VZ and hei long p ocesses ex end ou wa ds, o he pial su ace [ 83 ]. Ou e RGCs and in e media e p ogeni o s will hen es ablish he sub en icula zone (SVZ), which becomes one o he adul neu ogenic niches. RGCs will o igina e ansi ampli ying cells o inc ease neu onal p oduc ion [ 83 , 84 ]. NECs exi he cell cycle nea he en icula su ace and in ade he p epla e (PP—a p imo dial pla e abo e he VZ). Mig a ing neu ons mo e pas he subpla e, displacing his laye away om he Cajal-Re zius cells (CRCs), which emain adjacen o he pial su ace o he de eloping b ain in a cell-spa se a ea known as he ma ginal zone [ 85 ]. Dis inc p ojec ion neu on sub ypes a e bo n in sequen ial wa es o e he cou se o neu ogenesis [ 86 ]. As new co ical pla e neu ons a i e o he RGCs, hey mig a e pas he olde subpla e and co ical pla e neu ons be o e inse ing benea h CRCs [ 87 ]. This inside-ou a angemen o p ojec ion neu ons makes he oldes neu ons (co ical laye VI) closes and he younges neu ons (co ical laye II/III) a hes om hei bi hplace nea he en icle (Figu e 2B). This co ical expansion, despi e being conse ed wi hin all mammalian species, is di e en whe he o ganisms ha e a smoo h (lissencephalic, e.g., mouse, a ) o highly con olu ed (gy encephalic, e.g., e e , human) neoco ex [ 88 , 89 ]. One key di e ence is associa ed wi h he size o he neoco ex, which can be be e co ela ed wi h i s su ace a ea han wi h i s hickness, which only a ies sligh ly ac oss species [ 90 ]. B ain con olu ions appea ed as an e olu iona y solu ion o he p oblem o inc easing co ical su ace a ea (e.g., neu on numbe s) wi hou p ohibi i ely inc easing he size o he skull [ 91 ]. Ano he s iking in e species di e ence is ela ed o he expansion o he basal p ogeni o s [ 92 ]. In gy encephalic species, he SVZ can be u he dissec ed in wo dis inc ge minal zones: he inne SVZ, which la gely esembles he SVZ o lissencephalic oden s, and he ou e SVZ, which is absen in mos lissencephalic species [ 92 ]. This subdi ision o he SVZ has a emendous impac on he numbe o basal p ogeni o s con ained in each laye . Indeed, du ing peak s ages o emb yonic neu ogenesis, he ou e SVZ ha bo s up o ou imes as many p ogeni o s as he VZ and inne SVZ combined [ 93 ]. Howe e , his does no co ela e wi h a highe numbe o neu ons in he adul b ain. In ac , in la e de elopmen al s ages, a e emb yonic neu ogenesis is comple e, neu al p ogeni o s ansi ion in o a gliogenic mode, gene a ing as ocy es and oligodend ocy es [ 94 , 95 ]. CRCs will mig a e in o he neoco ical laye I o he co ex om non-co ical loca ions, whe eas p ojec ion neu ons bo n in he neoco ical VZ and SVZ, mig a e along adial p ocesses o each hei inal lamina des ina ions in he co ex [ 96 ]. The p esence o NSCs in mos CNS egions dec eases d ama ically a e emb yonic de elopmen bu , in many species, emains h oughou li e in localized neu ogenic niches [97–100]. Molecules 2019,24, 1350 9 o 59 3.2. Adul Neu ogenesis Adul NSCs can be mos ly ound in wo neu ogenic niches, he SVZ and he subg anula zone (SGZ) o he hippocampal den a e gy us (DG) (Figu e 2C) [101]. The exis ence o sel - enewing adul NSCs in he b ain led o he hypo hesis ha NSCs a e i-po en , ha ing he capaci y o gene a e neu ons, as ocy es, and oligodend ocy es. Howe e , he pionee ing in i o s udies in he adul hippocampus by E iksson and colleagues ha e only ound he gene a ion o neu ons and as ocy es, bu no oligodend ocy es [ 102 ]. On he o he hand, in i o s udies ocusing on he adul SVZ sugges ha NSCs can gi e ise o he h ee neu al cell ypes, bu whe he neu ons and glia a ise om dis inc s em cell lineages in i o is s ill unknown [103]. Adul NSCs a e mos ly quiescen in i o due o he speci ic cellula and molecula cha ac e is ics o he niches whe e hey eside, allowing hem o wi hs and me abolic s ess and o p ese e genome in eg i y o e long pe iods o ime [ 104 , 105 ]. The balance be ween he cy oa chi ec u e o he niches and he ac o s ha egula e quiescence and ac i a ion o NSCs is so delica e ha i has been p oposed ha umo igenic o b ain umo s em cells may a ise om an imbalance o hose ac o s [ 106 ]. In ac , bo h NSCs and umo igenic cells sha e many o he molecula pa hways ha egula e p oli e a ion, such as sonic hedgehog (shh) o Wn -signalling [106]. Despi e ha ing been shown o exis in se e al mammals since he 1960s (e.g., mice, a s, ca s, song bi ds, eesh ews, ma mose s, macaques), in humans, adul neu ogenesis has spa ked an in ense deba e ega ding i s exis ence [ 107 – 112 ]. Repo s o human neu ogenesis a e mos ly based on he analysis o neu ogenic ma ke s, namely doubleco in (DCX) and polysialic acid neu al cell adhesion molecule (PSA-NCAM) on pos -mo em b ain samples [ 102 , 113 – 115 ]. I has been sugges ed ha he di e ences ound in s udies whe e human adul neu ogenesis is ei he p o ed o disp o ed could be due o se e al ac o s a ound he ime o dea h, namely s ess ho mones, p o ein in eg i y and he gene al heal h s a e o subjec s; o e en he pos -mo em delay be ween sample collec ion and p epa a ion [ 116 , 117 ]. In ac , i has been shown in animal s udies ha he DCX signal becomes weak wi hin a ew hou s o pos -mo em delay, he e o e ime is a c ucial ac o on neu ogenesis s udies, impac ing he o e all analysis o da a [ 118 ]. A ecen s udy by So ells and colleagues (2018) showed ha adul neu ogenesis d ops o unde ec able le els wi h aging. This s udy was conduc ed wi h samples om pa ien s wi h epilepsy, whe e no mal hippocampal ci cui y and neu ogenesis is known o be dis up ed and had a pos -mo em delay o a ound 48 h be ween collec ion and ixa ion [ 113 ]. On he o he hand, in Bold ini e al. (2018) and mo e ecen ly in Mo eno-Jiménez e al. (2019) s udies, epo ed li elong neu ogenesis in humans. In hese s udies he pos -mo em delay was no longe han 26 h and samples we e collec ed om bo h con ol and pa hological subjec s [ 114 , 115 ]. Su p isingly, in Mo eno-Jiménez e al. (2019) s udy, samples om pa ien s wi h Alzheime ’s disease (AD) also ha e imma u e p ogeni o cells, i.e., DCX posi i e cells, al hough he numbe and ma u a ion o hese cells p og essi ely declined as AD ad anced, again ein o cing he idea ha issue handling is essen ial o he p ese a ion and de ec ion o neu ogenic ma ke s [115]. 3.2.1. Sub en icula Zone Ependymal cells a e o ganized in o ose e shaped s uc u es bo de ing he SVZ which is lining he la e al wall o he la e al en icles. The e a e h ee cell ypes ha mainly compose he SVZ niche: B cells, C cells and A cells. B cells (o adial glia-like NSCs) ex end adial p ocesses o con ac wi h blood essels and a single cilium h ough he ependymal ose es o con ac he ce eb ospinal luid in he en icula space [ 119 ]. These p ocesses allow he de ec ion o bo h in insic (e.g., shh, Wn o No ch-signaling) and ex insic ac o s (e.g., neu o ansmi e s, ho mones o g ow h ac o s) ha will signal o ei he p oli e a ion, di e en ia ion, o bo h [ 120 ]. B cells can di ide and di e en ia e in o C cells (o ansi ampli ying cells), which hen gene a e A cells (o neu oblas s) [ 121 ]. In oden s, neu oblas s mig a e down he os al mig a o y s eam (RMS) o he ol ac o y bulb whe e hey di e en ia e mainly in o GABAe gic in e neu ons and a e in eg a ed ei he in he GCL o in he pe iglome ula laye . Thus, SVZ neu ogenesis plays an impo an ole in he neu oplas ici y and Molecules 2019,24, 1350 16 o 59 b ain-de i ed neu osphe es, and ha in e leukin 1 (IL-1) signaling pa hway was in ol ed in his p ocess, emphasizing he neu oimmune in e ac ions o cannabinoid signaling [241]. O e all, mos e idence shows ha gene ic abla ion o cannabinoid ecep o s o ea men wi h CB1R and CB2R selec i e an agonis s leads o a dec ease in NSC p oli e a ion in he hippocampus and SVZ [ 175 , 213 , 217 ]. By con as , ei he di ec ac i a ion o cannabinoid ecep o s using syn he ic agonis s and/o an indi ec app oach aiming a inc easing eCBs, by inhibi ing hei deg ading enzymes, s imula es he o ma ion and ma u a ion o new neu ons in bo h adul niches [213,242,243]. The complexi y/ a iabili y o hese indings also illus a es ha s udy design, animal species, s ain, gende and/o compound selec i i y and dosage a e e y impo an when s udying he e ec s o cannabinoids in NSC egula ion. Mo eo e , da a dispa i y o many s udies in ol ing adul NSCs may in pa be explained by he a ying p ope ies o each NSC popula ion and he he e ogenei y wi hin each NSC pool, which sugges s ha eCB signals, ac ing in a pa icula spa ial and empo al manne , could di e en ially a ec he p oli e a i e capaci y o NSCs, limi ing he lineage speci ica ion o succeeding p ogenies. In ac , he e a e di e gences be ween he wo niche mic oen i onmen s ega ding he molecules ha egula e mo phogenesis, a es o di ision, sel - enewal and su i al which may accoun o he obse ed di e ences [244,245]. 5. Role o Cannabinoids in Neu ogenesis and Pa hophysiology Neu ological and men al diso de s comp ise a b oad ange o disabling condi ions wi h di e en pheno ypic ou pu s. Some symp oms o hese diso de s may a ise om ea ly impai men in neu al de elopmen o abe an adul neu ogenesis [ 246 ]. In ac , al e a ions in he mechanisms behind NSC egula ion in he emb yonic and adul b ain ha e been epo ed in bo h pa ien s and animal models o AD, Pa kinson’s disease (PD), MS, epilepsy and mood diso de s [247–251]. Despi e he ex ensi e e idence sugges ing ha bo h exogenous and endogenous cannabinoids egula e NSC p oli e a ion, which in u n may be a ec ed by disease loading, he link be ween NSCs, cannabinoids and b ain diso de s emains o be es ablished. This unclea ision may a ise om he poo / a ied design o p e-clinical s udies, he lack o pos -mo em analyses o b ains om pa ien s wi h neu ological diso de s as well as he lack o clinical s udies in ol ing cannabinoid usage. Howe e , se e al da a sugges ha manipula ion o cannabinoid signaling p omo es a ine- uned egula ion o NSCs, which is esul an om hei an i-in lamma o y and an ioxidan p ope ies. The e o e, eCBs may ha e an impac in delaying, p e en ing o es o ing some neu al de ici s in animal models ha mimic some ea u es o neu odegene a i e and psychia ic diso de s, he e o e, cons i u ing po en ial he apeu ic a ge s o neu o egene a ion. 5.1. Cannabinoids and Neu op o ec ion B ain damage and neu odegene a ion a e leading causes o long- e m disabili y, disease bu den and mo ali y wo ldwide [ 252 ]. They a e cha ac e ized by he p og essi e loss o speci ic neu onal subpopula ions in he CNS, wi h di e en clinical ea u es being exhibi ed and can esul om he na u al p ocess o b ain aging o b ain inju y/ auma. A ailable ea men s usually ac on ansien symp oma ic elie , being poo ly ac i e a igh ing he cellula e en s occu ing as b ain damage ad ances [ 253 ]. The e o e, i is essen ial o seek o molecules wi h disease-modi ying ac i i y ha ake in o conside a ion he mechanisms ha unde lie disease p og ession and enable he epai o neu onal loss. The neu op o ec i e po en ial o ECS- a ge ing compounds (e.g., cannabinoid agonis s o an agonis s, inhibi o s o eCB deg ada ion o biosyn hesis o o he modula o s) has been ex ensi ely in es iga ed o e he las 20 yea s [ 253 ]. This neu op o ec i e na u e o cannabinoids a ises no only om hei pleio opic p o ile, i.e., he capaci y o in e ac wi h neu omodula o y sys ems no di ec ly ela ed wi h he eCB signaling, bu also om he p esence o hese a ge s in key cellula componen s o he CNS (i.e., neu ons, as ocy es, mic oglia, oligodend ocy es and neu al p ogeni o cells) and b ain s uc u es like he blood–b ain ba ie [ 58 ]. These ea u es hen ansla e in o an abili y o es o e Molecules 2019,24, 1350 17 o 59 he CNS o a physiological homeos a ic s a e a e an acu e o ch onic pe u ba ion, by igh ing an a ay o cellula p ocesses caused by b ain insul s o damage, like exci o oxici y, inc eased s a e o neu oin lamma ion, oxida i e s ess and p o ein agg ega ion, as well as o he p ocesses ha in e e e wi h neu onal homeos asis and in eg i y [ 253 ]. Gi en he ela ionship be ween all hese pa hological cellula hallma ks, he p o ec ion o CNS componen s mus ac on all o mos o hese a ge s in a mul i ace ed manne . The e o e, cannabinoids a e aluable candida es o his s a egy. Excessi e elease o glu ama e gene a es accumula ion o oxic concen a ions o in acellula calcium and oxygen ee adicals, esul ing in exci o oxici y, a p ocess common o many b ain diso de s which o en leads o neu onal dea h [ 254 ]. A numbe o obse a ions indica e he abili y o cannabinoids o con ol glu ama e elease h ough he ac i a ion o CB1Rs and ha e e ealed a c ucial ole o his ecep o in exci o oxici y con ol, BDNF being a key media o o his p ocess [ 43 , 255 ]. O he s ha e also demons a ed ha cannabinoid-media ed neu op o ec ion agains exci o oxici y elies on CB1R and CB2R modula ion in glial cells [ 256 ]. Mo eo e , inhibi ion o eCB up ake wi h UCM707 was shown o ha e a p o ec i e ole agains AMPA-induced exci o oxici y h ough ac i a ion o CB1Rs, CB2Rs and PPARγs [257]. While he mechanisms o neu op o ec ion aimed a egula ing glu ama e homeos asis a e mainly due o CB1R ac ions, he an i-in lamma o y e ec s o cannabinoid-media ed p o ec ion a e mos ly a ibu ed o he modula ion o CB2Rs. Hence, he in ol emen o he ECS, pa icula ly o CB2Rs, in educing local o sys emic in lamma o y e en s is a c ucial pa o cannabinoid-media ed neu op o ec ion. Neu oin lamma ion is he p ocess by which he elease o cy o oxic agen s and cell dea h occu s a e acu e o ch onic CNS damage [ 258 ]. The egula ion by cannabinoids o mechanisms like modula ion o immune esponses and he elease o in lamma o y media o s was ex ensi ely e iewed in [ 259 ]. Fo ins ance, mouse mic oglial cell cul u es ea ed wi h CB2R selec i e agonis JWH015 showed a educ ion in in e e on- γ (IFN- γ )-induced up egula ion o CD40 exp ession, which lead o a dec ease in he p oduc ion o p oin lamma o y cy okines and an enhancemen o amyloid- β (A β ) phagocy osis [ 260 ]. Mo eo e , adminis a ion o CBD and WIN 55,212-2 was shown o educe he le els o p oin lamma o y cy okine IL-6 de i ed om A β exposu e [ 261 ]. Fu he s udies ha e epo ed ha o al adminis a ion o JWH-133, a po en CB2R agonis , dec eased mic oglial ac i a ion, p oin lamma o y ac o s COX-2 and umo nec osis ac o α (TNF- α ) mRNA exp ession and he co ical le els o A β in a ansgenic mouse model o AD [ 262 ]. In he con ex o aging, which is closely ela ed wi h an inc ease in neu oin lamma ion, aged a s adminis e ed wi h WIN 55,212-2 showed a educed numbe o ac i a ed mic oglia in he hippocampus and DG. Fu he mo e, he same ea men was ound o dec ease he mRNA le els o he IL-6, as well as he p o ein le els o he in lamma o y ac o s TNF-αand IL-1β[263]. In like manne , cannabinoid ecep o ligands a e o en epo ed as ha ing an ioxidan p ope ies because hey a e able o igh oxida i e s ess and educe eac i e oxygen species (ROS) load, p ocesses in ima ely associa ed wi h exci o oxici y and neu oin lamma ion. Fo example, ∆9 -THC exposu e was shown o escue he pha macologically-induced inhibi ion o mi ochond ial unc ion, ubiqui in p o easome and p oduc ion o ee adicals in a human neu oblas oma cell line [ 264 ]. Mo eo e , ea men wi h CBD p omo ed po en an ioxidan ac ions in bo h in i o and in i o s udies by educing ROS bu den [265,266]. In addi ion o he bene i s esul ing om di ec ac i a ion o he ECS, he abili y o eCBs o in e ac wi h o he molecules/sys ems can also p o ide neu op o ec i e ac ions. In ac , cannabinoid-media ed neu op o ec i e e ec s also esul om in e ac ions wi h ansc ip ion ac o s, neu o ophic ac o s, ecep o s o he PPAR amily o wi h elemen s o o he ansmission sys ems, like he se o onin 5-HT1A ecep o s o adenosine A2A ecep o s [267–272]. Impo an ly, he ECS has been shown o be in ol ed in he neu op o ec ion o NSCs and hei esul ing p ogeny. In ac , CB1Rs we e shown o be in ol ed in he exci o oxici y-induced neu al p ogeni o cell p oli e a ion and neu onal di e en ia ion [ 273 ]. Mo eo e , ac i a ion o CB2Rs was shown o inc ease he su i al o NSCs and p ogeni o cells, as well as o escue impai ed hippocampal Molecules 2019,24, 1350 18 o 59 neu ogenesis caused by ch onic insul by HIV-1 neu o oxic p o ein gp120 [ 226 ]. Mo e ecen ly, ac i a ion o GPR55 has demons a ed a neu o-immune egula o y ole o human and mu ine NSCs by p o ec ing hem agains ch onic in lamma ion in i o (wi h IL-1 β ea men ) and in i o (wi h ch onic LPS adminis a ion) [274]. Despi e he neu op o ec i e ac ions associa ed wi h he ECS modula ion, cannabinoid-induced neu o oxic e ec s ha e also been epo ed [ 252 ]. This inconsis ency may be due o nume ous ac o s, such as he se e i y and iming o he pa hologically-induced insul and, he kind o pha macological in e en ion implemen ed. The dosage and iming o adminis a ion o cannabinoids a e also o g ea impo ance, gi en ha high exposu e usually induces neu onal cell dea h [ 275 ]. Mo eo e , di e en cannabinoids ha e di e en mechanisms o ac ion depending on he ype o ecep o s hey modula e and he co esponding signaling pa hways. In he nex sec ions, illus a i e examples o ECS sys em modula ion in disease con ex will be desc ibed in mo e de ail (Supplemen a y Table S1). 5.2. Cannabinoids and B ain Diso de s 5.2.1. Alzheime ’s Disease La e-onse AD ( ≥ 65 yea s-old) is esponsible o abou 70% o all cases o demen ia [ 276 ]. The disease is cha ac e ized by a numbe o A β oligome iza ion and agg ega ion-induced neu o oxic mechanisms, including au hype phospho yla ion, neu oin lamma ion wi h eac i e gliosis (as o and mic ogliosis), exci o oxici y and oxida i e damage [ 277 – 279 ]. These changes, which p ima ily impac on he co ex and he hippocampal o ma ion, esul in dis up ed synap ic plas ici y, loss o synap ic unc ion, namely choline gic, and cell dea h [ 277 – 279 ]. Despi e being one o he mos debili a ing neu odegene a i e diso de s, p esen a ailable ea men op ions ha e ailed o s op o e en signi ican ly delay disease p og ession [ 278 ]. Due o i s b oad ange o ac ions a he PNS and CNS, modula ion o he ECS has been ex ensi ely discussed as a po en ial mul imodal disease-modi ying he apy o he managemen o complex mul i ac o ial condi ions such as AD ( e iewed in [ 7 , 280 , 281 ]). AD pa ien s classically show a slow-p og essing cogni i e impai men , no ably a ec ing sho - and long- e m memo y pe o mance, which a e highly dependen on hippocampal unc ion [ 277 , 282 , 283 ]. Howe e , clinical e idence assessing he po en ial bene i o cannabinoids on cogni i e decline is cu en ly lacking [ 284 ]. None heless, a ew pa ien ials ha e ocused on he use o he THC-based pha maceu ical o mula ion d onabinol (Ma inol ® ) o elie ing neu opsychia ic symp oms shown by mos demen ed indi iduals, deno ing a dec ease in agi a ion, noc u nal mo o ac i i y and agg essi e beha io s, as well as an inc ease in body weigh [285–288]. Changes in se e al componen s o he ECS ha e been desc ibed in AD pos -mo em samples and animal models o he disease. Despi e con adic ing esul s, hese changes appea o be dependen on he ype o cells, bu also on disease s age, and A β agg ega ion s a e [ 7 , 289 ]. In his ega d, an ini ial inc ease o CB1Rs is p oposed o occu , ollowed by a down egula ion a la e s ages [ 290 ]. In e es ingly, CB2Rs a e o e exp essed in mic oglia su ounding neu i ic plaques, ye dec eased in neu ons [ 50 , 291 , 292 ]. Inc eased 2-AG signaling is also obse ed a ound A β plaques in la e-AD, in associa ion wi h diminished MAGL ac i i y and enhanced DAGL exp ession [ 293 , 294 ]. In addi ion, augmen ed FAAH ac i i y and exp ession can be deno ed in as ocy es nea plaques, wi h subsequen educ ion o AEA [291]. How he egene a i e capabili y o he adul b ain is modula ed in aging and AD is s ill a ma e o deba e, wi h a iable esul s om in i o and in i o (bo h pha macological and ansgenic) animal models and pos -mo em human samples [ 295 ]. Howe e , mos e idence poin s o a deple ion o p oli e a ion, di e en ia ion and su i al o NSCs, as well as comp omised mo phology and ma u a ion o GCs in he DG o mouse models o AD [ 296 – 302 ]. Mo eo e , as o he ECS, al e a ions in AHN a e sugges ed o be dependen on disease p og ession and A β con o ma ion, being ini ially Molecules 2019,24, 1350 19 o 59 ele a ed as an a emp o compensa e o neu o oxici y and cell dea h, ye ading a la e disease s ages [303,304]. The use o di e en models o AD shows ex ensi e p omise ega ding he neu op o ec i e ole o cannabinoids. A ele an unc ion o hese compounds in educing amyloid bu den and associa ed neu o oxici y has been sugges ed in i o . ∆9 -THC is a compe i i e inhibi o o ace ylcholines e ase (AChE) ac i i y, po en ially p e en ing AChE-induced A β agg ega ion [ 305 ]. Bo h 2-AG and AEA, as well as CB1R/CB2R (WIN 55,212-2 and HU-210), and CB2R (JWH-133, JWH-015) agonis s, ha e been shown o p e en A β -induced oxici y, namely by p omo ing mic oglia-media ed A β clea ance [ 260 , 292 , 306 – 308 ]. Simila e ec s o CBD o PPAR γ ac i a ion we e also obse ed, demons a ing enhanced cell su i al, dec eased oxida i e s ess, and egula ion o A β p oduc ion and clea ance [309–313]. Fu he mo e, many au ho s ha e ocused on he cannabinoid-media ed an i-in lamma o y ac ions, mainly using ansgenic mouse models o AD o models ob ained by in ace eb al injec ions o A β o mice and a s. In hese models, neu oin lamma ion and eac i e gliosis a ound neu i ic plaques was shown o be e ec i ely down- egula ed by MAGL inhibi ion, WIN 55,212-2, CB1R agonis ACEA, CB2R agonis s MDA7 and JWH-133, CBD and THC+CBD [ 218 , 261 , 262 , 292 , 314 – 320 ]. Besides hese e ec s, a ious s udies using he same compounds and AD models ha e demons a ed lea ning and memo y imp o emen s, in asks ha signi ican ly ely on hippocampal unc ion, al hough some au ho s epo no e ec on Aβload [261,262,292,293,314–319,321–323]. In line wi h his, ∆9-THC and MAGL inac i a ion ha e been shown o dec ease he occu ence o neu i ic plaques in a ansgenic mouse model ca ying i e mu a ions ela ed o amilial AD (5xFAD) [324,325]. I is s ill unclea whe he cannabinoids migh ha e a posi i e impac on AD pa hology, pa ly h ough egula ion o AHN, ye a ew common pa hways may be men ioned. Some o he a o emen ioned an i-in lamma o y and neu op o ec i e ac ions o cannabinoids ha e been linked o he inhibi ion o glycogen syn hase kinase 3 β (GSK-3 β ) o e ac i a ion, which is known o p omo e au hype phospho yla ion and A β p oduc ion, and is a nega i e egula o o AHN [ 218 , 262 , 319 , 320 , 326 – 329 ]. In ac , CBD has been ound o supp ess eac i e gliosis and escue neu ogenesis in he DG o a s injec ed wi h A β 1-42 in a PPAR γ -dependen manne , likely h ough inac i a ion o GSK-3 β and subsequen escue o Wn / β -ca enin pa hway, an impo an egula o o AHN [ 218 , 320 , 330 , 331 ]. Adminis a ion o MDA7, a po en CB2R selec i e agonis , o AD ansgenic amyloid p ecu so p o ein/p esenilin 1 (APP/PS1) mice was obse ed o educe mic ogliosis, p omo e A β clea ance, es o e memo y pe o mance, synap ic plas ici y and Sox2 exp ession, a ansc ip ion ac o exp essed by NSCs in he DG [ 318 , 332 ]. Likewise, AEA was shown o enhance No ch-1 signaling, a known modula o o AHN, which was impai ed by A β in cul u ed neu ons [331,333]. A no ewo hy pa allelism can be made be ween a dose-dependen e ec o ∆9-THC on memo y and neu ogenesis, whe e low concen a ions o he compound appea o imp o e memo y unc ion and p omo e AHN, while highe doses seem de imen al ( ecen ly e iewed in [ 334 ]). Addi ionally, gi en he ele a ed densi y o cannabinoid ecep o s in he hippocampus and he ele ance o he ECS in egula ing AHN, i becomes e iden ha he he apeu ic alue o cannabinoids o AD pa hology may ely on es o ing abe an neu ogenesis [335]. Al hough p eclinical e idence has been suppo i e o he adminis a ion o cannabinoids o amelio a e AD pa hology, a clinical bene i emains o be assessed due o he limi ed numbe o clinical ials, wi h sho du a ion and low numbe o subjec s, ha ail o e alua e cogni i e pa ame e s, as well as bioma ke s o neu odegene a ion [ 281 , 336 ]. In addi ion, u u e s udies a e needed o assess long- e m sa e y and e ec i eness o na u al and syn he ic cannabinoids, speci ically in olde indi iduals wi h AD [ 280 , 336 ]. Impo an ly, he e is a p essing need o a be e comp ehension o he unde lying mechanisms conce ning he in e ac ion o cannabinoids in AD and hippocampal NSC modula ion, namely using speci ic neu ogenic ma ke s. Molecules 2019,24, 1350 20 o 59 5.2.2. Pa kinson’s Disease PD is cha ac e ized by a p og essi e degene a ion and subsequen loss o DA neu ons in he subs an ia nig a pa s compac a (SN) [ 337 ]. These neu ons compose he b ain mo o sys em, being esponsible o he ini ia ion o mo emen and he ewa d pa hway, by inne a ion o he s ia um [ 338 ]. The p esence o Lewy bodies, which a e mainly o med o alpha-synuclein ( α Syn) agg ega es, ha e been iden i ied as a p e equisi e o he pos -mo em diagnosis o bo h he p e-symp oma ic and symp oma ic phases o he pa hological p ocess unde lying PD. These agg ega es ha e been iden i ied as belonging o wo dis inc ca ego ies, he b ains em- and he co ical-de i ed, wi h he la e ype being mo e s ongly immuno eac i e o α Syn [ 339 – 341 ]. Symp oma ically, PD is a p og essi e mo emen diso de ha causes muscle igidi y, emo s, b adykinesia and shu ling gai [ 342 ]. I can also cause demen ia, especially in ad anced s ages [ 338 ]. The mo o dys unc ions, which a e he main ea u e in PD, become symp oma ic when ≈ 60% o neu ons a e al eady los [ 341 ]. Al hough in he as majo i y o cases PD is idiopa hic, epidemiological e idence sugges s ha en i onmen al oxins such as pes icides inc ease PD isk [ 340 , 343 ]. Howe e , in some cases, PD is associa ed wi h inhe i ed mu a ions in PD- ela ed genes, such as α -Synuclein (SNCA), pa kin (PARKIN), PTEN-induced pu a i e kinase p o ein 1 (PINK1), ubiqui in ca boxyl- e minal es e ase L1 (UCH-L1) and leucine- ich epea kinase 2 (LRRK2) [ 344 ]. Cu en he apeu ics o PD ely mos ly on he use o pha macological agen s, mainly h ough he use o L-DOPA, a dopamine p ecu so [ 345 ]. These a e o en used o imp o e mo o symp oma ology o PD pa ien s, ende ing no e ec i e cu e o PD. The e o e, he de elopmen o new s a egies has been he ocus o cu en PD esea ch. Ta ge ing he ECS may p o e as an al e na i e he apy o imp o e mo o symp oms, as PD pa ien s epo ed an amelio a ion in b adykinesia, accompanied by a educ ion in muscle igidi y and emo s a e cannabinoid in ake [ 346 ]. These epo s a e suppo ed by h ee majo pieces o e idence. Fi s , he basal ganglia and ce ebellum, b ain a eas esponsible o he con ol o mo emen , which a e highly a ec ed in PD, exp ess CB1R, CB2R and TRPV1R [ 347 – 349 ]. Second, i has been shown ha mo o ac i i y is ep essed by he s ong inhibi o y ac ion p omo ed by a a ie y o cannabinoids, which a e esponsible o ine- une he ac i i y o a ious classical neu o ansmi e s [ 350 – 353 ]. Finally, e idence shows ha ECS signaling is al e ed in he basal ganglia o humans and in animal models o PD [ 354 – 356 ]. These clinical-based e idence a e suppo ed by obus p e-clinical da a which indica es ha he ECS has a neu op o ec i e ole in PD [ 357 , 358 ]. One s udy, using a o enone-induced a model o PD supplemen ed wi h β -ca yophyllene (BCP), a na u ally occu ing CB2R agonis , showed a dec ease in he le els o p oin lamma o y cy okines and in lamma o y media o s. These esul s we e u he suppo ed by an inc ease in y osine hyd oxylase immuno eac i i y, which illus a ed he escue o he DA neu ons and a educ ion in he ac i a ion o glial cells [359]. In human PD pos -mo em s udies, he endogenous pool o adul NSCs was shown o be signi ican ly a ec ed, speci ically in he SGZ, sugges ing a po en ial e ec o dopamine on NSC p oli e a ion and su i al, as e iewed by [ 161 , 360 ]. New e idence sugges s ha adul NSCs a e also impai ed in animal models o PD, suppo ing da a om human s udies. Al hough he p ecise mechanisms and e ec s o hese changes a e no ye ully unde s ood, α Syn and aging we e shown o dec ease adul neu ogenesis h oughou he se e al s ages o PD [361–363]. One o he ea lies s ages o PD is cha ac e ized by a non-mo o symp om, namely hyposmia o anosmia, which is he loss o he sense o smell, being epo ed in 90% o pa ien s [ 364 ]. Al e a ions in ol ac ion in PD seem o be ela ed wi h changes in cen al ol ac o y p ocessing, which could be explained by α Syn pa hology being p esen in he ol ac o y bulb long be o e Lewy bodies a e de ec ed in he SN [ 341 ]. In ac , neu ogenesis in he SVZ and ol ac o y bulb was shown o be impai ed in a ansgenic mouse model exp essing he human α Syn ca ying he A30P mu a ion, whe e signi ican ly ewe newly gene a ed neu ons we e obse ed in he ol ac o y bulb [ 365 ]. O he s udies, using he Pa kinson 6-hyd oxydopamine (6-OHDA) a model ha e shown ha 6-OHDA induced SN DA degene a ion and had a majo impac on SGZ neu ogenesis [ 366 , 367 ]. These epo s sugges ha dopamine deple ion educes NSC p oli e a ion and consequen ly adul neu ogenesis [368]. Molecules 2019,24, 1350 21 o 59 The e o e, po en ia ing he in insic pool o NSCs has been p oposed as an al e na i e po en ial PD he apy. Se e al s udies, wi h con adic o y indings, ha e been ocusing on s imula ing he p oduc ion o DA neu ons om he SVZ and SGZ. In ac , i was shown ha he adminis a ion o D1 and D3 ecep o agonis s in he 6-OHDA a model, p oduced an inc ease in SGZ and SVZ cell p oli e a ion, espec i ely [ 367 , 369 ]. Adding o ha , a D3 ecep o agonis also inc eased DA newbo n neu ons in he SN, leading o he imp o emen o mo o impai men s [ 369 ]. Ano he s udy ailed o induce SN DA neu ogenesis using he D2/D3 ecep o agonis p amip exole, howe e i p omo ed ol ac o y bulb DA neu ogenesis [ 370 ]. Ano he g owing s a egy is he use o human plu ipo en s em cells o induce DA di e en ia ion. These can be de i ed om ea ly p e-implan a ion emb yos (emb yonic s em cells, ESCs) o by ep og amming adul soma ic cells (induced plu ipo en s em cells, iPSCs), and hen di e en ia ed in o midb ain DA neu ons using ecen ly de eloped p o ocols [ 371 , 372 ]. Howe e , b ain implan a ion o hese cells equi es in asi e su gical echniques and gene a es side e ec s (e.g., g a -induced dyskinesias) wi h signs o disease- ela ed pa hology in he ansplan ed cells being isible yea s a e implan a ion [373–375]. A cannabinoid induc ion o DA di e en ia ion om NSCs is s ill unde deba e [ 207 , 215 ]. One ecen s udy compa ed AEA wi h ∆9 -THC and concluded ha , using highe doses o hese compounds, he unc ional ma u a ion and DA speci ica ion om human co d blood-de i ed iPSCs was signi ican ly comp omised [207]. To conclude, in PD, i has been shown in se e al s udies wi h bo h human pos -mo em samples and animal models ha bo h neu ogenic niches a e signi ican ly impai ed by α Syn pa hology o DA deple ion [ 360 , 361 ]. Replenishing he DA neu onal loss has been p o ing a challenge o he scien i ic communi y, whe he by using he endogenous pool o NSCs, o by a ge ing he ECS, o p omo e neu ogenesis a speci ic and selec i e imepoin s. The ECS may s ill be applied clinically in o de o amelio a e PD symp oma ology due o he a o emen ioned neu op o ec i e p ope ies o cannabinoids and he e o e imp o ing he quali y o li e o PD pa ien s [358,376,377]. 5.2.3. Mul iple Scle osis MS is one o he mos ecu en diso de s o he CNS. Despi e i s unknown e iology, an immune esponse and consequen in il a ion o immune cells in o he CNS oge he wi h demyelina ing e en s culmina es in oligodend ocy e loss and neu onal degene a ion. Some o he esul ing symp oms a e spas ici y, emo s, a axia, bladde dys unc ion and neu opa hic pain, wi h a high impai men o he quali y o li e o he pa ien [ 378 – 380 ]. MS pa ien s ha consumed cannabis epo ed elie ega ding se e al o hese symp oms, highligh ing a possible ole o cannabinoids in MS [ 380 – 385 ]. Fu he mo e, he neu op o ec i e e ec s o hese molecules in MS has been ho oughly desc ibed in he li e a u e, since hey a e able o diminish oligodend ocy e dea h and inc ease emyelina ion whils ha ing an an i-in lamma o y ole [ 231 , 386 , 387 ]. Changes in eCB le els and also in he le els o i s ecep o s and deg ading enzymes, FAAH and MAGL, we e obse ed bo h in blood and pos -mo em b ain samples o MS pa ien s and in animal models o MS, such as he expe imen al au oimmune encephalomyeli is (EAE) model, in di e en s ages o disease [379,383,388–393]. S udies using EAE-induced mice whe e CB1Rs and CB2Rs we e gene ically dele ed o pha macologically inhibi ed show ele a ed neu odegene a ion and poo e an i-in lamma o y esponses accompanied by an inc ease in EAE se e i y and mo o impai men [ 379 , 386 , 394 – 396 ]. The po en ial a ge s o ECS modula ion in MS, namely he deg ading enzymes and anspo e s which ac i ely pa icipa e in his mechanism by con olling he le els o eCBs ha e been a ma e o s udy [ 380 , 397 – 399 ]. Howe e , he exac mechanisms o he ac ions o cannabinoids in MS a e s ill no o ally known. Using he Theile mu ine encephalomyeli is i us-induced demyelina ing disease (TMEV-IDD) mice, i was possible o obse e ha he modula ion o he ECS by inhibi ion o AEA up ake esul ed in an imp o emen o mo o pe o mance, educ ion o mic oglial/mac ophage ac i a ion and p oin lamma o y cy okine elease, accompanied by an inc ease in eCB signaling [400]. Molecules 2019,24, 1350 22 o 59 Recen ly, i has been shown ha CBD a enua es EAE pa hology by ac i a ing an i-in lamma o y myeloid-de i ed supp esso cells in he pe iphe y, o by modula ing he inc ease o an i-in lamma o y and dec ease o p oin lamma o y cy okines, bo h in i o and in i o [ 401 , 402 ]. Addi ionally, ea men wi h WIN 55,212-2, a CB1R/CB2R non-selec i e agonis , was ound o a enua e he in e ac ion be ween leukocy es and endo helial cells, which is necessa y o immune cells o in il a e he CNS, he e o e inhibi ing in il a ion. Mo eo e , by using selec i e CB1R and CB2R an agonis s, i was obse ed ha he e ec on leukocy e a icking exe ed by cannabinoids is igge ed by CB2R ac i a ion [ 403 , 404 ]. Fu he mo e, as i is in ima ely- ela ed wi h immune esponses, CB2R selec i e ac i a ion was shown o imp o e EAE pheno ype by dec easing disease se e i y and incidence [ 405 ]. Addi ionally, he accumula ion o CD4 + T cells in he b ain and spinal co d is also dec eased in hese animals, wi h a esponse depending on he ime o adminis a ion, a an ea ly o la e imepoin o disease cou se [405]. Th oughou he yea s, nume ous clinical ials wo ldwide ha e been using cannabis-based d ugs in an a emp o ea MS symp oms. Th ee main ac i e p inciples de i ed om cannabis o mula e hese d ugs: d onabinol (Ma inol ® ), a syn he ic isome o ∆9 -THC, nabilone (Cesame ® ), a syn he ic analogue o ∆9 -THC and nabiximols (Sa i ex ® ), a 1:1 mix o ∆9 -THC and CBD [ 380 ]. Sa i ex ® consis s o an o al sp ay app o ed in some Eu opean coun ies and Canada o he ea men o spas ici y and pain elie in MS pa ien s, wi h mild- o-mode a e side e ec s ha occu sca cely in pa ien s [ 379 , 380 , 406 – 416 ]. Ne e heless, no ial has shown a slowe disease p og ession in MS pa ien s p esc ibed wi h THC-based d ugs and, hence, he e a e s ill no e idence o i s neu op o ec i e e ec in humans [379,417,418]. Concomi an ly, in MS he e is myelin damage and oligodend ocy e loss, and hus, inding new mechanisms o p omo e bo h e-myelina ion and OPC di e en ia ion, ei he om p ecu so s p esen in he b ain pa enchyma o de i ed om SVZ NSCs is c ucial, since OPCs a e able o mig a e and pa ially emyelina e lesioned a eas [ 249 , 419 – 421 ]. Cells om he oligodend oglial lineage a e di ec ly modula ed by cannabinoids in dis inc ma u a ion s ages, anging om he egula ion o OPC su i al, p oli e a ion, mig a ion and di e en ia ion o he modula ion o ma u e oligodend ocy e su i al and myelina ing capaci y [ 422 , 423 ]. Fo ins ance, i has been obse ed ha OPCs exp ess CB1Rs and CB2Rs and ha cannabinoids p omo e OPC su i al and oligodend ocy e di e en ia ion h ough he PI3K/Ak /mTORC1 signaling pa hway, which is known o pa icipa e in he myelina ion p ocess [ 229 , 231 , 422 , 424 – 429 ]. CBD has also been shown o be a modula o o his pa hway and i s adminis a ion o EAE mice was shown o dec ease he in il a ion o in lamma o y immune cells in o he CNS and o p omo e he phospho yla ion o PI3K, Ak and mTOR, oge he wi h he inhibi ion o MAPK signaling pa hway, leading o an an i-in lamma o y esponse and neu onal su i al [423]. Al hough se e al s udies ha e looked a he ela ionship be ween cannabinoids and oligodend ocy e di e en ia ion unde in lamma o y-demyelina ing condi ions, he e is s ill a majo gap conce ning he abili y o SVZ-de i ed NSCs o be modula ed by cannabinoids and di e en ia e in o OPCs, which could be use ul o MS he apeu ics and should be add essed in u u e s udies [ 235 ]. 5.2.4. Epilepsy Epilepsy is a neu ological diso de cha ac e ized by a pe sis en p edisposi ion o gene a e epilep ic seizu es which a e o en associa ed wi h neu obiological, cogni i e, psychological and social consequences [ 430 , 431 ]. An epilep ic seizu e can be de ined as an abno mal excessi e and/o synch onous neu onal ac i i y in he b ain, which ins iga es a ansien beha io al al e a ion, comp ising a my iad o signs and symp oms (such as loss o awa eness, s i ening, among o he s) [ 430 ]. Al hough mos pa ien s ha e idiopa hic epilepsy, seizu es can be induced by lesions o insul s ha impac no mal b ain unc ion and ac i i y. The main causes o epilepsy include lesions o s uc u al al e a ions, such as s oke, umo , auma ic b ain inju y, in ec ious diseases, me abolic al e a ions, au oimmune diseases and gene ic mu a ions [ 430 , 432 ]. Mo e han 500 genes ha e been linked o Molecules 2019,24, 1350 23 o 59 epilepsy, including 84 genes ha di ec ly cause epilepsies o synd omes wi h epilepsy as one o hei co e symp oms [433]. Epilep ogenesis is he mul i ac o ial p ocess ha unde lies he de elopmen o spon aneous seizu es. I occu s be o e and pe sis s beyond he i s unp o oked episode and can p og ess o e se e al yea s in humans [ 430 , 432 , 434 ]. The mechanisms behind his p ocess a e s ill no comple ely unde s ood bu include a widesp ead o al e a ions in bo h neu onal and non-neu onal cells, leading o molecula and s uc u al changes ha esul in he dys unc ion o neu onal ci cui s [ 430 , 434 , 435 ]. The main al e a ion is an imbalance be ween exci a ion and inhibi ion in he neu onal ci cui s, h ough an inc ease in exci a o y neu o ansmission, as well as a dec ease in inhibi o y neu o ansmission, esul ing in a s a e o con inuous hype exci abili y [436]. Un il ecen ly, epilepsy ea men was p ima ily ocused in s opping seizu es, dis ega ding he unde lying mechanisms behind he disease. None heless, his pa adigm is changing, wi h esea ch con e ging in o e o s on inding new an icon ulsan s, wi h bo h neu op o ec i e and an iepilep ic p ope ies. Acco ding o ecen da a, he ECS and i s cons i uen s may ep esen such he apeu ic a ge s [ 437 , 438 ]. In ac , epilepsy o en induces al e a ions in he ECS, pa icula ly a he le el o CB1R exp ession and p oduc ion o eCBs [ 437 ]. Indeed, cu en e idence in mice sugges s ha CB1R exp ession is up egula ed a GABAe gic synapses and down egula ed a glu ama e gic synapses in epilepsy, al hough no consensus has been eached [ 439 , 440 ]. Mo eo e , epilepsy in humans a ec s he p oduc ion o endogenous eCBs by in e e ing wi h he le els o cannabinoid enzymes like DAGL and MAGL, which is sugges i e o a pi o al ole o cannabinoid one in his disease [ 441 , 442 ]. Eme ging clinical e idence, mos ly coming om epidemiological da a and case epo s, depic s he o e all posi i e e ec s o cannabinoid adminis a ion using a high a io o CBD:THC in he managemen o esis an epilepsy [ 443 – 445 ]. Fu he mo e, cannabinoids and hei endogenous coun e pa s ha e been associa ed wi h epilepsy ea men , wi h se e al s udies using a ious cannabinoid-based d ugs in animal models o epilepsy [ 446 – 451 ]. Fo example, ea men wi h WIN 55,212-2 (a CB1R/CB2R agonis ) was shown o p e en ch onic epilep ic hippocampal damage in a s by a enua ing he se e i y and equency o spon aneous ecu en seizu es [ 452 ]. In pa icula , s udies using CB1R ligands ha e shown ha he ac i a ion o his ecep o can delay he p og ession o seizu e se e i y as well as he equency o spon aneous epilep i o m ac i i y [ 446 , 447 , 450 ]. Mo eo e , s udies using condi ional CB1R KO models ha e demons a ed ha eCB signaling plays an impo an ole in he e mina ion o epilep ic ac i i y, depending on he neu onal subpopula ion, whils ha ing no impac in he ini ia ion o hype exci abili y [ 451 ]. Las ly, i has also been shown ha he MAGL inhibi ion leads o a delay in he de elopmen o gene alized seizu es in he kindling model o empo al lobe epilepsy [ 449 ]. Apa om hei in insic an icon ulsan p ope ies, cannabinoids ha e been shown o po en ia e o he an i-epilep ic d ugs [453–455]. Impo an ly, epilep ic seizu es we e shown o p omo e abe an AHN in he g anula laye , cha ac e ized by a ansien inc ease in he p oli e a ion o neu al p ogeni o s, GCL dispe sion, pe sis ence o hila basal dend i es and ec opic placing o adul -bo n GCs [ 430 , 435 ]. E idence shows ha p olonged seizu es induce an inc ease in cell p oli e a ion in he SGZ (up o 5–10 old), las ing o se e al weeks [ 435 , 456 – 458 ]. Howe e , app oxima ely h ee o ou weeks a e he pe sis en seizu e pe iod, p oli e a ion e u ns o baseline le els o e en dec eases o subs an ially lowe a es when compa ed o con ol animals [ 435 , 457 , 459 ]. The same has been obse ed in humans, whe e i was desc ibed ha se e e seizu es du ing ea ly childhood p omp a dec ease in AHN, nega i ely a ec ing no mal b ain de elopmen and u he p og ession o epilep ogenesis [ 460 ]. Whe he he mechanism in pa ien s is simila o hose ound in animal models, i.e., a ansien inc ease in he p oli e a ion o neu al p ogeni o s ollowed by a educ ion o neu ogenesis, is no known, ins iga ing u he s udies o add ess his ma e [435,460,461]. The al e a ions in neu ogenesis go beyond cell p oli e a ion, also a ec ing ma u a ion and mig a ion o adul -bo n neu ons. A e s a us epilep icus, which consis s o a single epilep ic seizu e las ing mo e han i e minu es o wo o mo e seizu es wi hin a i e-minu e pe iod wi hou eco e y Molecules 2019,24, 1350 24 o 59 o consciousness, newbo n GCs mig a e owa ds he den a e hilus o he molecula laye ins ead o in eg a ing in o he GCL, bo h in oden models and pa ien s wi h epilepsy [ 457 , 459 , 462 – 464 ]. Mo eo e , he co ec ma u a ion o he GCs upon epilep ic s imuli does no occu , being obse ed an accumula ion o hila basal dend i es, which a e no mally a ea u e o imma u e cells. This abno mal ma u a ion may be one o he mechanisms unde lying he hype exci abili y o adul -bo n GCs and he ci cui s whe e hey in eg a e [ 465 – 468 ]. Impo an ly, cannabinoids, when combined wi h an iepilep ic d ugs, can inc ease neu ogenesis in he piloca pine mouse model o epilepsy [ 469 , 470 ]. In ac , co-adminis a ion o ACEA, a selec i e CB1R agonis , wi h sodium alp oa e, a classic an iepilep ic d ug, was shown o signi ican ly inc ease he numbe o p oli e a ing cells in he same model [ 469 , 470 ]. Howe e , u he s udies a e needed o asce ain whe he his inc ease in neu ogenesis is no abe an and can con adic he disease symp oms. None heless, hese esul s show p omise by sugges ing ha NSC modula ion by cannabinoids can be a po en ial a ge in his diso de . As a o emen ioned, epilepsy ea men is an e ol ing and eme ging opic wi h he sea ch o new d ugs and he apeu ic a ge s e e inc easing [ 471 ]. One key aspec ha can be a ge ed is he seizu e-induced neu ogenesis, which can also help amelio a e he disease como bidi ies [ 472 ]. Indeed, a ge ing abe an AHN may educe ecu en seizu es and es o e cogni i e de ici s, namely memo y impai men [ 473 – 475 ]. Since i is known ha he ECS can, on one hand, egula e adul neu ogenesis and, on he o he hand, ha e an impac in epilep ic ea men , u he s udies a e equi ed o in es iga e he pu a i e mechanisms by which cannabinoids ha e an impac in he ea men o epilepsy. Mo eo e , unde s anding how cannabinoid-induced modula ion o NSCs may ha e neu oplas ic e ec s and whe he his can be used as an an i-epilep ic ea men is highly ele an . 5.2.5. Anxie y/Dep ession Anxie y and dep ession a e neu opsychia ic condi ions wi h high p e alence wo ldwide, i s symp oms ange om i i abili y, anhedonia, di icul ies in concen a ing as well as dis u bances in appe i e, sleep, dec eased p oduc i i y and inc eased suicide isk [476]. Al e a ions a he le el o NSCs, especially in he hippocampus, a e well known co ela es o bo h anxie y and dep essi e diso de s [ 477 ]. The ECS is a known modula o y key playe in NSC egula ion, d ugs a ge ing his sys em induce mood al e a ions [ 478 , 479 ]. On he o he hand, AHN has been shown o be equi ed o he e ec s o an idep essan s, sugges ing ha acili a ion o neu ogenesis can be bene icial o ch onic an idep essan ea men [ 480 ]. In line wi h his, se e al indings sugges he in ol emen o cannabinoids in hese neu ogenesis-p omo ed long-las ing an idep essan e ec s [ 481 ]. Simila o he ac ions o con en ional an idep essan s, cannabinoid modula ion was shown o p omo e an idep essan and anxioly ic e ec s [ 479 , 482 ]. The e o e, in ecen yea s he e has been a ma ked inc ease in he in e es o using he ECS as a po en ial he apeu ic a ge in hese diso de s [213,481,483,484]. In e es ingly, changes in eCB le els ha e also been epo ed in a ec i e diso de s. The ci cula ing le els o hese molecules ha e been ound o be diminished in indi iduals diagnosed wi h dep essi e and anxie y diso de s [ 485 , 486 ]. Likewise, in animal models o dep essi e-like beha io he e is a signi ican o e all dec ease in b ain AEA le els, sugges ing an impai men o eCB one [ 487 – 489 ]. In line wi h his, polymo phisms in he gene encoding o FAAH (FAAH), ha e been linked o an inc eased isk o dep essi e and anxie y diso de s [ 490 , 491 ]. Mo eo e , in animal models o dep essi e-like beha io , es ain s ess induces a signi ican inc ease o FAAH exp ession in nume ous b ain egions associa ed wi h a ec i e unc ioning [ 492 – 494 ]. Da a ega ding 2-AG is less clea : while i was ound o be diminished in he some egions, as a consequence o ch onic mild s ess (CMS), i has been obse ed o be inc eased in se e al key egions o he limbic sys em such as he amygdala, in esponse o he same s ess exposu e [ 492 – 494 ]. In acco dance wi h his las inding, MAGL exp ession has been ound o dec ease o e ime, in esponse o pe sis en s ess [ 494 ]. These esul s ha e led some esea che s o p opose ha 2-AG p oduc ion may be s imula ed in si ua ions o pe sis en s ess, as a bu e mechanism agains possible s ess-induced neu onal dys egula ion [494,495]. Molecules 2019,24, 1350 25 o 59 Acu e and in e mi en adminis a ion o CB1R agonis s is known o biphasically modula e anxie y, in bo h humans and oden s. Low doses a e known o be anxioly ic, and highe doses anxiogenic [ 496 , 497 ]. A he beha io le el, acu e adminis a ion o CB1R agonis s such as ∆9 -THC, CBC, ACEA, HU-210, CP 55,940 and WIN 55,212-2, ha e been mos ly ela ed o imp o emen s in he pe o mance o animals in se e al beha io al asks, as well as he o e all pheno ype o animal models o dep essi e-like beha io [ 498 – 504 ]. In con as , ch onic exposu e o CB1R agonis s ha e been shown o induce ma ked al e a ions ha a e age- and gende -dependen [ 505 , 506 ]. Speci ically, epidemiological da a sugges s ha while adul ch onic use may be a isk ac o o anxie y and dep essi e diso de s, his dele e ious e ec is no as p onounced as in adolescen s [ 507 – 510 ]. Indeed, ch onic adolescen use s ha e been consis en ly ound o ha e a highe isk o being diagnosed wi h anxie y and/o dep essi e diso de s, and ha his isk is bigge in emales [ 511 – 513 ]. Cu iously, in animal models, he opposi e is sugges ed, since in adolescen animals no pe sis ing al e a ions a he le el o anxie y ha e been ound bu dep essi e-like beha io has been ound o be ma kedly inc eased [ 505 , 506 , 514 ]. Impo an ly, his las ing impai men in dep essi e-like beha io seems o be la gely es ic ed o emale animals, and is accompanied by impai men s in hippocampal neu ogenesis, which is e e sed by ea men wi h he FAAH inhibi o URB597 [ 506 , 515 – 517 ]. In con as , adul animals ch onically exposed o po en ull agonis s o cannabinoid ecep o s show pe sis ing anxioly ic and an idep essan e ec s, along wi h enhanced AHN, unde sco ing he impo ance o age in he long- e m e ec s o cannabinoids [518–521]. The e ec s o CB1R an agonism/in e se agonism a e much mo e consis en . Despi e some animal beha io al e idence o anxioly ic- and an idep essan -like e ec s, imonaban (SR141716) and AM251 ha e been well desc ibed as p omo e s o anxie y and dep essi e-like symp oms in bo h oden s and humans when ch onically adminis e ed [ 494 , 522 – 527 ]. Indeed, imonaban , ini ially comme cialized o he ea men o obesi y, was ecalled a e being ela ed o inc eases in dep essi e/anxious symp oms [ 528 ]. Addi ionally, in oden s, his compound has been demons a ed no only o p omo e dep essi e-like beha io , bu also o educe cell p oli e a ion and su i al in he hippocampus [526]. The e is e idence sugges ing ha single nucleo ide polymo phisms in he CB1R coding gene (CNR1) a e ela ed o an inc eased isk o s ess-p ecipi a ed dep essi e episodes, as well as esis ance o an idep essan d ugs [ 529 , 530 ]. In acco dance, hese polymo phisms a e mo e p e alen among indi iduals diagnosed wi h mood diso de s [491]. In line wi h his, CMS induces a dec ease in CB1R exp ession in he hippocampus, hypo halamus and s ia um [ 489 , 531 ]. Fu he mo e, CB1R KO oden s p esen a cha ac e is ic anxious/dep essi e-like beha io al p o ile, accompanied by a 50% dec ease in hippocampal NSC p oli e a ion [213,525,532]. Li le esea ch has been published so a on he e ec s o CB2R agonis s on anxie y- and dep essi e-like beha io s, wi h a ew con adic o y epo s. Some au ho s epo CB2R agonis s o ha e anxioly ic e ec s (JWH-015 and BCP), o he s epo anxiogenic e ec s (JWH-133), con as ing wi h o he s ha epo no e ec s (GW405833) [ 533 – 538 ]. Mo eo e , CB2R agonis s like BCP, JWH-133 and oleamide, may ha e an idep essan -like e ec s, despi e some epo s inding no changes wi h he ea men (JWH-015) [ 533 , 534 , 539 ]. Cu iously, gi en he e ec s o CB2R ac i a ion desc ibed abo e, he e a e epo s showing CB2R an agonis AM630 as ha ing anxioly ic and an idep essan -like e ec s [538–540]. Likewise, no much is known abou he in ol emen o CB2Rs in he pa hophysiology o dep essi e and anxie y diso de s. In humans, a s udy ound an associa ion be ween a polymo phism in he CB2R coding gene (CNR2) and a numbe o psychia ic and immune diso de s, which a e o en como bidi ies [ 541 ]. Mo eo e , animals ca ying his polymo phism a e less sensi i e o he CB2R-media ed e ec s o WIN 55,212-2 and 2-AG, sugges ing a possible link be ween impai ed CB2R unc ioning and al e ed beha io al pheno ypes [ 542 ]. In ac , CB2R KO animals p esen inc eased anxie y- and dep essi e-like beha io s [ 543 , 544 ]. Simila ly, animals o e exp essing CB2Rs no only show educed anxious- and dep essi e-like beha io al pheno ypes, bu also a e ac ually esis an o Molecules 2019,24, 1350 32 o 59 35. Piomelli, D. The molecula logic o endocannabinoid signalling. Na . Re . Neu osci. 2003 ,4, 873–884. [C ossRe ] [PubMed] 36. Howle , A.C.; B ei ogel, C.S.; Childe s, S.R.; Deadwyle , S.A.; Hampson, R.E.; Po ino, L.J. 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