Exploring the singularity of human neurons: keep calm and carry on

Frontiers in Synaptic Neuroscience 01 frontiersin.org Exploring the singularity of human neurons: keep calm and carry on BaptisteLibé-Philippot * Aix-Marseille Université, CNRS, Developmental Biology Institute of Marseille (IBDM), NeuroMarseille, Marseille, France The human brain’s increased cognitive abilities are underpinned by evolutionary adaptations at the molecular, cellular, and circuit levels of neural structures. This perspective explores how protracted neuronal development and divergent cell intrinsic neuronal properties, including neuronal excitability, contribute to human neurobiological singularity. Those cellular aspects rely on molecular evolutionary innovations, including evolution of gene regulation and gene duplications that play critical roles in prolonging synaptogenesis and reducing neuronal excitability. These molecular evolutionary innovations are shown to interact with core neurodevelopmental molecular pathways linked to neurodevelopmental disorders. Furthermore, complementary multimodal and multiscale approaches offer promising platforms to study these processes and develop species-relevant therapeutic strategies. They include exvivo acute brain slices and organotypic cultures which offer emerging tools for understanding human species-specificities and neural disorders. KEYWORDS human brain evolution, neuronal development and maturation, human gene duplicates, synaptic neoteny, neuronal excitability, cerebral cortex, exvivo brain sections, neurodevelopmental disorders Introduction Near my laboratory, located in the Calanques of Marseille (France), lies the underwater Cosquer Cave. Within its submerged depths, prehistoric paintings created between 27,000 and 14,000BC provide a striking glimpse into the distant past of Homo sapiens. The artwork depicts various animals—horses, ibex, deer, bison, aurochs, seals, and penguins—as well as human symbols, including genital representations and stencils of human hands (Clottes etal., 1992). While the precise meaning of these anthropological signs remains elusive, they undoubtedly represent the cognitive and cultural evolution that distinguishes Homo sapiens from other primate, hominid and archaic hominin species. Notably, these features, including abstract thinking, cultural transmission, social learning, cooperation, and language (Richerson etal., 2021; Sherwood and Gómez-Robles, 2017; Lancaster, 2024; Zeberg etal., 2024), are underpinned by neurobiological substrates that evolved alongside morphological, metabolic, and immune system changes (Zeberg etal., 2024; Pollen etal., 2023). What is the biological substrate responsible for such evolutionary advancements? Over the past four decades, research has pointed to the increased size of the human brain, particularly the cerebral cortex—the outermost layer of the brain involved in sensory processing and higher cognitive functions—as a central element in the evolution of human cognition (Figure1A). This expansion has been associated with a larger number of neurons and more complex cytoarchitecture within the cerebral cortex, which together contribute to the increased cognitive abilities of humans. These changes primarily result from the evolution OPEN ACCESS EDITED BY Viktor Szegedi, Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Hungary REVIEWED BY Ikuo K. Suzuki, The University of Tokyo, Japan *CORRESPONDENCE Baptiste Libé-Philippot [email protected] RECEIVED 24 July 2025 ACCEPTED 28 August 2025 PUBLISHED CITATION Libé-Philippot B (2025) Exploring the singularity of human neurons: keep calm and carry on. Front. Synaptic Neurosci. 17:1672646. doi: 10.3389/fnsyn.2025.1672646 COPYRIGHT © 2025 Libé-Philippot. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Mini Review PUBLISHED DOI 10.3389/fnsyn.2025.1672646 02 October 2025 02 October 2025 Libé-Philippot 10.3389/fnsyn.2025.1672646 Frontiers in Synaptic Neuroscience 02 frontiersin.org of neurodevelopmental processes, especially those governing neural proliferation, neurogenesis, and fate determination during the prenatal period (Sherwood and Gómez-Robles, 2017; Lancaster, 2024; Libé-Philippot and Vanderhaeghen, 2021; Lindhout et al., 2024; Vanderhaeghen and Polleux, 2023; Kelley and Pașca, 2022; Namba and Huttner, 2024). However, despite significant advances in our understanding of these developmental processes, relatively little is known about the evolution of the fundamental building blocks of the brain—the neurons themselves—and the circuits they form (Lancaster, 2024; Vanderhaeghen and Polleux, 2023; Libé-Philippot et al., 2024). Humans share most cortical neuron types with other mammalian and primate species, yet these neurons exhibit morphological and physiological differences that may be central to the evolution of human cognition. These differences are thought to be linked to species-specific gene expression patterns and human-specific modifiers of ancestral molecular mechanisms, including pathological ones (Lancaster, 2024; Pollen etal., 2023; Vanderhaeghen and Polleux, 2023; Libé-Philippot etal., 2024; Wallace and Pollen, 2024). Carry on slowly: protracted synaptogenesis and enhanced learning abilities A particularly striking feature of human neurodevelopment is the protracted pace of neuronal development. This phenomenon, known as heterochrony, bradychrony, or neoteny, refers to the delayed maturation of key neurodevelopmental processes, including corticogenesis and synaptic maturation, in humans compared to other primate species (Sherwood and Gómez-Robles, 2017; Lancaster, 2024; Libé-Philippot and Vanderhaeghen, 2021; Lindhout et al., 2024; Petanjek etal., 2011; Zhou etal., 2024; McNamara, 2012). Notably, neoteny of the synaptogenesis—the process through which neurons form connections in a highly plastic manner (Sherwood and GómezRobles, 2017; Waites etal., 2005)—is thought to bethe foundation for the enhanced learning abilities characteristic of Homo sapiens (Gould, 1992; Bufill etal., 2011). Each step of this protracted neurodevelopment could follow different modalities of heterochrony, influenced by various mechanisms, including epigenetic regulation, metabolic processes, protein targeting to synapses, and human-specific modifiers that regulate these processes (Libé-Philippot and Vanderhaeghen, 2021; Casimir etal., 2024; Ciceri and Studer, 2024). For example, synaptogenesis takes approximately 5–10 years in humans, compared to months in macaques and weeks in mice, while corticogenesis lasts months in humans, as opposed to weeks in macaques and days in mice (Libé-Philippot and Vanderhaeghen, 2021; Lindhout etal., 2024; LibéPhilippot etal., 2024). Furthermore, it is conceivable that different brain regions undergo varying rates of developmental maturation, with synaptogenesis showing more pronounced heterochronicity in areas such as the prefrontal cortex—region associated with higher cognitive functions (Petanjek etal., 2011)—compared to primary sensory and motor areas (Sherwood and Gómez-Robles, 2017). Understanding the molecular and cellular substrates underlying this protracted neurodevelopment is pivotal for uncovering the distinctive cognitive abilities of humans. It is also critical to understanding fundamental bases of neurodevelopmental disorders since they may beintimately linked to disturbed pace of synapse development, in particular in autism spectrum disorder and schizophrenia (Penzes etal., 2011). Previous studies have shown that neurons derived from human, chimpanzee and mouse pluripotent stem cells and xenotransplanted into mouse cerebral cortex, mature at their own pace (Libé-Philippot and Vanderhaeghen, 2021; Vanderhaeghen and Polleux, 2023; Linaro et al., 2019; EspunyCamacho etal., 2013; Marchetto etal., 2019; Gaspard etal., 2008). This suggests that the pace of neuronal development is primarily driven by cell-intrinsic, species-specific mechanisms, included at the synaptic maturation level (Libé-Philippot etal., 2024). What molecular mechanisms underpin these changes in the pace of development? Many of the developmental processes, cell types, and gene expression patterns involved in neurodevelopment are highly conserved across vertebrate species, with basic neuronal and synaptic functions shared even among distant metazoan taxa (Lancaster, 2024; Libé-Philippot and Vanderhaeghen, 2021; Zhou etal., 2024; Tosches, 2021). However, many of the genomic innovations specific to the human lineage are linked to neurodevelopmental and neuronal physiological processes. On examples are mutations in cis-regulatory elements that represent about 1% of the genomic differences between Homo sapiens and chimpanzees and that result in novel gene expression patterns (Pollen et al., 2023; Libé-Philippot and Vanderhaeghen, 2021; Lindhout etal., 2024; Vanderhaeghen and Polleux, 2023; Kelley and Pașca, 2022; Libé-Philippot etal., 2024; Zhou etal., 2024; Whalen and Pollard, 2022; King and Wilson, 1975). This includes human gain enhancers in the more than 3,000 human accelerated regions, which are largely non-coding regulatory genomic regions, highly conserved between mammalian species but divergent in the human genome, that are particularly active in neural processes (Pollen et al., 2023; Libé-Philippot and Vanderhaeghen, 2021; Lindhout etal., 2024; Vanderhaeghen and Polleux, 2023; Kelley and Pașca, 2022; Libé-Philippot etal., 2024; Zhou etal., 2024). These regulatory changes can lead to species-specific differential patterns of gene expression. For instance, OSTN (osteocrin) is a muscle and bone secreted protein but expressed in the brain only in primate species. It regulates the protracted maturation of the dendritic tree (Ataman etal., 2016). This could beexplained by the presence in the genomes of primate species of binding sites to the transcription factors of the MEF2 family, involved in synaptic maturation (Ataman etal., 2016). Interestingly, MEF2A was identified to display a protracted developmental expression pattern in the human cerebral cortex compared to other primate species (Liu et al., 2012). Striking experimental works revealed human-specific deletions in cis-regulatory elements of CBLN2 (cerebellin 2), and higher retinoic acid signaling in the primate prefrontal cortex, which led to CBLN2 higher levels of expression leading to increase synapse formation and cortical connectivity (Shibata etal., 2021; Shibata etal., 2021). Another level of molecular evolutionary novelties relies on segmental gene duplications, such as species-specific gene duplicates (Pollen et al., 2023; Libé-Philippot and Vanderhaeghen, 2021; Lindhout etal., 2024; Vanderhaeghen and Polleux, 2023; Kelley and Pașca, 2022; Libé-Philippot etal., 2024; Zhou etal., 2024; Bailey etal., 2002; Soto etal., 2025). One well-documented example of such a genomic innovation is the SRGAP2 (SLIT-ROBO Rho GTPase Activating Protein 2) gene family, specifically the human-specific SRGAP2B and SRGAP2C genes. These genes, which arose during the emergence of Homo species, have been shown to induce protracted synaptic maturation and enhanced neuronal connectivity when Libé-Philippot 10.3389/fnsyn.2025.1672646 Frontiers in Synaptic Neuroscience 03 frontiersin.org overexpressed in mouse cortical neurons, leading to enhanced cortical connectivity and learning abilities (Lancaster, 2024; Pollen etal., 2023; Libé-Philippot and Vanderhaeghen, 2021; Vanderhaeghen and Polleux, 2023; Kelley and Pașca, 2022; Namba and Huttner, 2024; Charrier etal., 2012; Schmidt etal., 2021). It was recently confirmed that SRGAP2B and SRGAP2C are essential for protracted synaptic maturation, as demonstrated by the knockdown of their expression in human cortical neurons xenotransplanted into the mouse cerebral cortex (Figure1C) (Libé-Philippot etal., 2024). Surprisingly, these experiments revealed that the acceleration of synaptic development was more pronounced than expected: at 18 months posttransplantation, the neurons had reached synaptic densities similar to those observed in 5–10-year-old children. Furthermore, the experiments uncovered a novel molecular mechanism involving a competition between the synaptic proteins SRGAP2A and SYNGAP1 (Synaptic Ras GTPase-activating protein 1), which regulate the timing of synaptogenesis in mammals, with SRGAP2B and SRGAP2C acting as human-specific modifiers (LibéPhilippot etal., 2024). SYNGAP1 is a major gene responsible for intellectual disability and autism spectrum disorder (Gamache etal., 2020). One cellular phenotype of SYNGAP1 haploinsufficiency is a precocious synaptic development or disrupted neoteny (Vermaercke etal., 2024), as observed in some forms on autism spectrum disorder (Penzes etal., 2011). Interestingly, SYNGAP1 postsynaptic synaptic accumulation and the phenotype of accelerated synaptogenesis could berescued while performing SRGAP2A knock-down in a SYNGAP1 haploinsufficiency genetic background (Libé-Philippot etal., 2024), opening possibilities for future therapeutic approaches (Figure1C). Those recent studies highlight several levels of breaks that act on the protraction of the synaptic development. While the evolution of gene regulation (e.g., epigenetics, non-coding genomic regions) acts on differences in the pattern and pace at the transcription step (Pollen etal., 2023; Libé-Philippot and Vanderhaeghen, 2021; Lindhout etal., 2024; Vanderhaeghen and Polleux, 2023; Kelley and Pașca, 2022; LibéPhilippot etal., 2024; Zhou etal., 2024; Ciceri and Studer, 2024; Ataman etal., 2016; Liu etal., 2012; Shibata etal., 2021; Shibata etal., 2021), and are easily assessed by transcriptomic studies, additional non-genetic post-transcriptional breaks act on the protein abundance at the synapse. Indeed, the developmental pace of variation in the synaptic abundance of some proteins does not fit with the variation of the transcripts, suggesting post-transcriptional and/or translational and/or protein stability regulation (Wang etal., 2023). Such regulation, involves the activity of small GTPases that could mediate synapse targeting (Wang etal., 2023) or the interaction between humanspecific proteins with their ancestors that can lead to their degradation (Libé-Philippot etal., 2024; Assendorp etal., 2024). This indicates that future studies on (local) translation, protein stability, protein co-trafficking and cell-state dependant synaptic targeting, beyond FIGURE1 Human modifiers of neuronal development and physiology modulate neuronal disease pathways. (A) Evolution of the brain size. (B) Species-specific neuronal features. (C) Human-specific modifiers of synapse development and of neurodevelopmental disorder molecular pathway. (D) Human modifier of neuronal excitability and of neurological disorder molecular pathway. Libé-Philippot 10.3389/fnsyn.2025.1672646 Frontiers in Synaptic Neuroscience 04 frontiersin.org cross-species transcriptional comparisons, could bebeneficial for a deeper understanding on the evolution of synaptic development and structure. One could wonder why several levels of mechanisms or breaks evolved in the same direction, e.g., a protracted neuronal and synaptic maturation. On one hand, this could ensure the robustness (Hiesinger and Hassan, 2018) of this key human developmental feature. On the other hand, a strong robustness to excessive variations, e.g., neotenic disruption, allows subtle variations (Hiesinger and Hassan, 2018). One could extrapolate that different scales of subtle variations could bekey in the development of human circuits: (1) variations between neurons/ synapses that may becrucial to achieve developmental robustness (Hiesinger and Hassan, 2018), (2) it could beinvolved in different paces of development between neuronal compartments (e.g., dissociate the pace of development of synapse subtypes, synapses versus axon, dendrites, etc.), or (3) between cerebral cortex area (e.g., a higher protraction in the prefrontal cortex versus motor cortex). Moreover, one could imagine that such profusion of breaks could have participated in the evolvability of Homo species. Keep calm: reduced neuronal excitability and enhanced computational properties While much attention has been paid to the developmental aspects of human neuronal evolution, less is known about the species-specific physiological characteristics of human cortical neurons and the underlying mechanisms that give rise to these traits (Vanderhaeghen and Polleux, 2023; Libé-Philippot et al., 2024). Cross-species comparisons from ex vivo brain sections, originating from non-pathological surgical resections provided human specificities at the morphological, physiological and connectivity levels, in the cerebral cortex (pyramidal excitatory neurons and GABAergic interneurons), in the hippocampus (connectivity) and in the cerebellum (Purkinje cells) (Libé-Philippot etal., 2023; BeaulieuLaroche etal., 2021; Beaulieu-Laroche etal., 2018; Kalmbach etal., 2018; Wilson etal., 2025; Watson etal., 2025; Mohan etal., 2015; Eyal etal., 2014; Deitcher etal., 2017; Hunt etal., 2023; Chartrand etal., 2023; Busch and Hansel, 2023; Masoli etal., 2024; Campagnola etal., 2022; Szegedi etal., 2020; Molnár etal., 2016; Wilson etal., 2025; Oláh etal., 2025; Csemer etal., 2023; Kalmbach etal., 2021; Wilbers etal., 2023), suggesting co-evolution of brain regions, for which remains the question of the underlying mechanisms (common molecular innovations, adaptation, etc.). Morphologically, human neurons are larger, exhibiting more elaborate dendritic arborization and a greater number of synapses leading to higher neural connectivity compared to other primates. These features are thought to contribute to the enhanced computational properties of human neurons (Vanderhaeghen and Polleux, 2023; Libé-Philippot etal., 2024). At the electrophysiological level, human neurons are more compartmentalized, less excitable, and capable of generating long trains of action potentials when engaged in cognitive tasks, compared to neurons in other mammals and primates (Figure 1B) (Vanderhaeghen and Polleux, 2023; Libé-Philippot etal., 2024). Fine tuning of intrinsic neuronal excitability is critical since disturbed intrinsic neuronal excitability is intimately linked to neurological disorders, including epilepsy, migraine and neurodegenerative disorders (Wijesinghe and Camp, 2011). More attention will beprobably paid in the coming years at the scales beyond neuronal properties, for instance circuit structure and computational properties. Those divergent cellular features should rely on molecular novelties, including divergence in cis-regulatory elements, even though a comprehensive molecular substrate for those evolutionary divergent features is far to beunderstood. These changes can lead to differential patterns of gene expression. For instance genes differentially expressed in human cortical pyramidal neurons compared to other primate and hominid species are notably linked to synaptic compartments’ structure and physiology (Jorstad etal., 2023). Moreover, among human duplicated genes, FRMPD2B and LRRC37B should play a critical role in the divergence of human neurons, FRMPD2B in synaptic signaling (Soto etal., 2025) and LRRC37B in neuronal excitability (Libé-Philippot etal., 2023). It was recently shown that human cortical neurons exhibit greater diversity in the excitability of their axon initial segment (AIS), the subcellular compartment where action potentials are initiated (LibéPhilippot etal., 2023). The consequence at the circuit and information processing levels remains to beexplored. This lower excitability could be an adaptive response to the increased neural connectivity in humans, resulting in higher accuracy of information processing. This could contribute to allowing for sustained trains of action potentials during cognitive tasks without compromising signal fidelity. This altered excitability may also modulate information processing at both the neuronal and circuit levels by influencing neuronal gain and increasing neuronal diversity (Libé-Philippot etal., 2024). A pivotal discovery was the identification of the hominid-specific transmembrane protein LRRC37B (Leucine Rich Repeat Containing 37B), which is localized to the AIS of a subset of human cortical neurons. Strikingly, LRRC37B was found to reduce neuronal excitability at the level of the AIS (Libé-Philippot et al., 2023). Interestingly, humans possess more than 15 paralogs of the LRRC37 gene family, which encodes transmembrane proteins with leucine-rich extracellular domains. Among these paralogs, LRRC37B is specific to humans and hominids (including chimpanzees), differing from the other paralogs and the ancestral Lrrc37a found in other amniotes (Libé-Philippot etal., 2023; Giannuzzi etal., 2013). The ancestral Lrrc37a gene is not expressed in the mouse cerebral cortex and LRRC37B transcript is expressed at higher levels in human cortical pyramidal neurons than in chimpanzees (Libé-Philippot etal., 2023). Moreover, the LRRC37B protein is not detected at the AIS of the chimpanzee cortical pyramidal neurons (Figure1D) (Libé-Philippot etal., 2023). The AIS, a crucial site enriched with voltage-gated sodium channels (Na v ), which are essential for action potential generation (Libé-Philippot etal., 2023). Using various experimental approaches, it was demonstrated that LRRC37B interacts with two key modulators of Na v channels—secreted FGF13 (fibroblast growth factor 13) isoform A (FGF13A) and the transmembrane protein SCN1B (β-subunit of Nav)—to modulate neuronal excitability (Libé-Philippot etal., 2023). Ex vivo electrophysiological recordings showed that LRRC37B overexpression in mouse cortical pyramidal neurons enhances the inhibitory effect of FGF13A on Na v channels, thus decreasing neuronal excitability at the AIS (Figure1D) (Libé-Philippot etal., 2023). One could imagine that exploring how to modulate the LRRC37B–FGF13A–SCN8A interaction to act on neuronal excitability, could beuseful to cure epileptic disorders. Libé-Philippot 10.3389/fnsyn.2025.1672646 Frontiers in Synaptic Neuroscience 05 frontiersin.org Therefore, LRRC37B is a human species-specific modulator of AIS and neuronal excitability and it acts by concentrating FGF13A function on Na v channels (Figure1D) (Libé-Philippot etal., 2024; Libé-Philippot etal., 2023). This work opens an avenue to address many questions in the future, including the consequences of a diverse lower excitability of the AIS to the neural circuit function and information processing. Another aspect that this study highlight is the heterogeneity in the protein composition of a neuronal compartment, i.e., a subpopulation of any neuronal subtype express LRRC37B protein at their AIS (LibéPhilippot etal., 2023), between cortical neurons. This follows other studies showing a higher diversity or specialization of neurons in the human cerebral cortex compared to other species (Jorstad etal., 2023; Berg etal., 2021). This challenges the definition of neuronal type defined by transcript marker expression, as recently done in the zebrafish in which transcriptionally similar neurons can befunctionally diverse (Shainer etal., 2025). One could wonder which transcriptional and post-transcriptional mechanisms evolved in humans leading to potential higher molecular diversity within neuronal populations. This can involve for instance cell-state dependent mechanisms, translational or sub-compartment protein targeting mechanisms, morphological/synaptic innervation dependent mechanisms, to bestudied further. Regarding the potential impact of such higher diversity or specialization, one could wonder whether this led to changes in neural processing, including the reliability and robustness of neural information processing, functional specialization, complexity of neuronal information transmission, robust learning (Wu etal., 2025; Perez-Nieves etal., 2021; Gjorgjieva etal., 2016). Novel experimental models and computational biology should help in the near future to elucidate which of those functional properties could have emerged from the human neuronal evolution, beyond expanded cortical size. Species-specific sensitivities to neurodevelopmental and brain disorders Interestingly, many of the cellular processes involved in human neural evolution and the genes that distinguish the human lineage are closely tied to neurodevelopmental disorders, aging, and brain diseases (Libé-Philippot and Vanderhaeghen, 2021; Zhou etal., 2024; Vickery etal., 2024; Douaud etal., 2014). For instance, dysregulation of neurodevelopmental processes, such as those occurring during neural proliferation and that evolved in humans, can lead to defects in the final brain cytoarchitecture, resulting in conditions such as microcephaly and macrocephaly (Libé-Philippot and Vanderhaeghen, 2021). Mutations in human accelerated regions, while divergent to all other mammalian species, are enriched in individuals with neurodevelopmental disorders and underlie for instance 5% of consanguineous cases of autism spectrum disorders (Doan etal., 2016). For instance, MEF2 genes and their binding sites are linked to autism spectrum disorder (Chaudhary etal., 2021). Some other genes displaying human species-specific developmental patterns of expression like CBLN2 code for proteins that are ligands to receptors tightly linked to neurodevelopmental disorders (e.g., neurexins) (Südhof, 2023), suggesting that they could mediate species-specific sensitivities to those disorders. Some human duplicated genes reside in genomic hotspots linked to neurodevelopmental disorders, including autism spectrum disorder (Soto et al., 2025). Other human duplicated genes, and notably SRGAP2C and LRRC37B, are loss-of-function intolerant, suggesting strong levels of purifying selection (Soto etal., 2025). They could act as species-specific modifiers of molecular pathways implicated in neurodevelopmental disorders (Libé-Philippot etal., 2024; Assendorp etal., 2024). Specifically, the SRGAP2 gene family, and particularly the human-specific genes SRGAP2B and SRGAP2C, were functionally linked to SYNGAP1 and CTNND2, two synaptic proteins associated with intellectual disabilities, autism spectrum disorders, and Cri-duChat syndrome (Libé-Philippot etal., 2024; Assendorp etal., 2024). Additionally, the hominid-specific protein LRRC37B was demonstrated to interact with FGF13A, SCN1B and SCN8A that are involved in epilepsy, Dravet syndrome, and autism spectrum disorder (Libé-Philippot etal., 2023). These results highlight the possibility of species-specific sensitivities to neurodevelopmental and neurological disorders that that can becritical in the diagnosis, patient management and therapeutical approaches. In our knowledge, neurodevelopmental disorders like autism spectrum and schizophrenia have not been described in nonhuman primates, even though common genetic and social behavioral traits have been identified compared to other species, including chimpanzees (Li etal., 2021; Faughn etal., 2015; Yoshida etal., 2016; Crow, 1997). It would mean that such disorders are the consequence of genomic trade-offs between neural circuit evolution and harmful effects in the variation of their development and structure (Sikela and Searles Quick, 2018). This apparent evolution of vulnerability to neurodevelopmental disorders could result from human speciesspecific causes of such disorders (e.g., genetic evolution and protracted development), natural selection in nonhuman species against such variations, or on the fact that the definition of such disorders are based on behavioral traits expanded in humans (e.g., language). Moreover, humans display species-specific gray matter decline linked to aging in cerebral cortex area that diverged in size compared to chimpanzees (notably, the prefrontal and frontal cerebral cortex) (Vickery etal., 2024). While several animal species, including non-human primates, display age-related amyloid-β and tau accumulation, there is debate on whether cellular loss and behavioral disorders linked to Alzheimer’s disease might bea human-specific disorder (Devinsky etal., 2018; Finch and Austad, 2015). Human exvivo approaches for basic research and drug development How studying human brain basic development, function, and disorders? Answering this question necessitates multimodal and multiscale approaches. Indeed, depending on the scale of the study, from genes to cell to circuit to behavior, one could consider human individuals themselves, primary samples, human pluripotent stem cell-based models (2D differentiations, organoids, assembloids) or animal experimentation (Figure2). These approaches differ not only on the accessible scales but also on the stages and neural processes they can address. Moreover, every biological technology and approach cannot beaccessible by each of those approaches on its own. In this context, spare human brain tissues obtained from neurosurgical procedures can beused in acute conditions to address Libé-Philippot 10.3389/fnsyn.2025.1672646 Frontiers in Synaptic Neuroscience 06 frontiersin.org cellular properties, morphologies, “omic” (genomic, epigenetic, transcriptomic, proteomic, metabolomic, lipidomic, etc.) and molecular questions (Libé-Philippot etal., 2023; Beaulieu-Laroche etal., 2021; Beaulieu-Laroche etal., 2018; Kalmbach etal., 2018; Wilson etal., 2025; Watson etal., 2025; Mohan etal., 2015; Eyal etal., 2014; Deitcher etal., 2017; Hunt etal., 2023; Chartrand etal., 2023; Busch and Hansel, 2023; Masoli etal., 2024; Campagnola etal., 2022; Szegedi etal., 2020; Molnár etal., 2016; Wilson etal., 2025; Oláh etal., 2025; Csemer etal., 2023; Kalmbach etal., 2021; Wilbers etal., 2023; Wilbers etal., 2023; Kerkhofs etal., 2018; Wierda etal., 2024; Lee etal., 2023; Kim etal., 2023; Bernard etal., 2004; Buchin etal., 2022; Ting etal., 2018; Gidon etal., 2020; Lee etal., 2023; Szegedi etal., 2024; Bocchio etal., 2019; Szegedi etal., 2023; Szegedi etal., 2017; Yang etal., 2025; Yang etal., 2024; Szegedi etal., 2016; Barzó etal., 2025; Guet-McCreight etal., 2023; Rich etal., 2022; Mertens etal., 2024; Moradi Chameh etal., 2021; Goriounova etal., 2018). Interestingly, neuronal physiology can becombined with post-hoc morphological and connectivity reconstructions, protein immunostaining and transcriptomic approaches. Such approaches can beof interest to address questions on mature and aging tissues because of the protracted neuronal development that make other human models’ immature, and on a genetic and epigenetic human and aged background (Figure 2). The sections come from cortical and hippocampal regions, mostly, and from drug-resistant or cancer patients. Importantly, fresh autopsies could bean alternative source of tissue, with control conditions and offering more diverse brain regions (Verwer etal., 2002; Verwer etal., 2002; Plug etal., 2024). This enabled to study non-pathological regions (e.g., tissues with no lesions surrounding an epileptic focus or a tumor) (Libé-Philippot etal., 2023; Beaulieu-Laroche etal., 2021; Beaulieu-Laroche etal., 2018; Kalmbach etal., 2018; Wilson etal., 2025; Watson etal., 2025; Mohan etal., 2015; Eyal etal., 2014; Deitcher etal., 2017; Hunt etal., 2023; Chartrand etal., 2023; Busch and Hansel, 2023; Masoli etal., 2024; Campagnola etal., 2022; Szegedi etal., 2020; Molnár etal., 2016; Wilson etal., 2025; Oláh etal., 2025; Csemer etal., 2023; Kalmbach etal., 2021; Wilbers etal., 2023; Wilbers etal., 2023; Kerkhofs etal., 2018; Wierda etal., 2024; Lee etal., 2023; Kim etal., 2023; Ting etal., 2018; Gidon etal., 2020; Lee etal., 2023; Szegedi etal., 2024; Bocchio etal., 2019; Szegedi etal., 2023; Szegedi etal., 2017; Yang etal., 2025; Yang etal., 2024; Szegedi etal., 2016; Barzó etal., 2025; Guet-McCreight etal., 2023; Mertens etal., 2024; Moradi Chameh etal., 2021; Goriounova etal., 2018), pathological regions (e.g., epileptic focus) (Bernard etal., 2004; Buchin etal., 2022; Rich etal., 2022) and cross-species comparisons (e.g., rodents versus nonhuman primates versus humans) (LibéPhilippot etal., 2023; Beaulieu-Laroche etal., 2021; Beaulieu-Laroche etal., 2018; Kalmbach etal., 2018; Wilson etal., 2025; Watson etal., 2025; Mohan etal., 2015; Eyal etal., 2014; Deitcher etal., 2017; Hunt etal., 2023; Chartrand etal., 2023; Busch and Hansel, 2023; Masoli FIGURE2 Experimental models to study human brain development, aging, disorders and evolution. In green accessible aspects of the models, in orange limited access, in green accessible aspects. Libé-Philippot 10.3389/fnsyn.2025.1672646 Frontiers in Synaptic Neuroscience 07 frontiersin.org etal., 2024; Campagnola etal., 2022; Szegedi etal., 2020; Molnár etal., 2016; Wilson etal., 2025; Oláh et al., 2025; Csemer et al., 2023; Kalmbach etal., 2021; Wilbers etal., 2023). Interestingly, those acute recordings enable to assess the acute effect of organic compounds (e.g., caffein, receptor agonists/modulator or channel blockers) (Kerkhofs etal., 2018; Bocchio et al., 2019; Szegedi etal., 2023; Yang etal., 2025; Yang etal., 2024), ideally in a dose–response manner, on electrophysiological properties. This is of particular interest for drugs that target proteins selectively expressed or higher expressed in humans, like HCN channels (Kalmbach etal., 2018; Szegedi et al., 2023), or for confirmation of results got in non-human animals (Yang etal., 2025). Importantly, some studies described evolution of electrophysiological properties across life (Barzó etal., 2025; GuetMcCreight etal., 2023). They identified the age of the individual as a critical parameter of changes with critical changes in most of the electrophysiological parameters in the first year of life, of resting membrane potential until 40 years old and input resistance changes from this age (Barzó etal., 2025), as well as increase in sag amplitude and decrease in spike rate with age (50 years old) (Guet-McCreight etal., 2023), suggesting that reproducibility and clinical translation of drug delivery experiments needs to pay attention of these 3 periods of life (first year of life, 1–40/50 years old, >40/50 years old). Moreover, some electrophysiological properties correlates with IQ scores (Goriounova etal., 2018), suggesting that other metadata should benoted while doing such experiments. Organotypic cortical sections were successfully cultured for a couple of weeks exvivo on artificial or human cerebrospinal fluids with stable neuronal morphology and electrophysiological properties (Verwer etal., 2002; Verwer etal., 2002; Plug etal., 2024; Schwarz etal., 2019; O’Connor etal., 1997; Eugène etal., 2014; Andersson etal., 2016; Ting etal., 2018; Schwarz etal., 2017; McGeachan etal., 2025; McGeachan et al., 2025; Bak et al., 2024; Wickham et al., 2020; Andersson etal., 2016; Vormstein-Schneider etal., 2020; Chaichana etal., 2007; Jung etal., 2002; Ravi etal., 2019; Mendes etal., 2018; Sebollela etal., 2012; Barth etal., 2021; Da Seixas Silva etal., 2017; Da Seixas Silva etal., 2017; Verwer, 2003; Wu etal., 2008; Taylor etal., 2024; Le Duigou etal., 2018; McLeod etal., 2023; Andrews etal., 2020; Subramanian etal., 2017; Mukhtar etal., 2025; Chen etal., 2023; Graybuck etal., 2021; Ting etal., 2018; Schünemann etal., 2025). Such approaches enable to explore basic and pathological mechanisms in human brain tissues from the molecular to the cell to the circuit levels (Figure2). They open the possibility to perform dynamic experiments (e.g., live imaging, calcium activity, electrophysiology) (Wickham etal., 2020; Andersson etal., 2016; Le Duigou etal., 2018; Andrews etal., 2020; Subramanian etal., 2017; Mukhtar etal., 2025) with genetic manipulations (e.g., viral injection delivery, optogenetics) (O’Connor etal., 1997; Eugène etal., 2014; Andersson etal., 2016; Ting etal., 2018; Andersson etal., 2016; Vormstein-Schneider etal., 2020; Le Duigou etal., 2018; McLeod etal., 2023; Andrews etal., 2020; Mukhtar etal., 2025; Graybuck etal., 2021; Ting etal., 2018) or drug applications (e.g., dose– response) (Ravi etal., 2019; Mendes etal., 2018; Taylor etal., 2024; Andrews etal., 2020), as well as cell grafting (Wu etal., 2008), with control conditions from the same individual. They have mostly been performed in adult conditions, non-pathological (e.g., outside an epileptic focus) (Verwer etal., 2002; Verwer etal., 2002; Schwarz etal., 2019; Andersson etal., 2016; Ting etal., 2018; Schwarz etal., 2017; Bak etal., 2024; Wickham etal., 2020; Andersson etal., 2016; Le Duigou etal., 2018; Chen etal., 2023; Graybuck etal., 2021; Ting etal., 2018; Schünemann etal., 2025) and pathological (e.g., epilepsy, tumor environment, neurodegenerative conditions) (Schwarz etal., 2019; O’Connor etal., 1997; Eugène etal., 2014; McGeachan etal., 2025; McGeachan etal., 2025; VormsteinSchneider etal., 2020; Chaichana etal., 2007; Jung etal., 2002; Ravi etal., 2019; Mendes etal., 2018; Sebollela etal., 2012; Barth etal., 2021; Da Seixas Silva etal., 2017; Da Seixas Silva etal., 2017; Verwer, 2003; Wu etal., 2008; Taylor etal., 2024; Plug etal., 2024) with drugs or viral applications (Plug etal., 2024), but exploring neurodevelopmental stages (McLeod etal., 2023), including fetal stages (McLeod etal., 2023; Andrews etal., 2020; Subramanian etal., 2017; Mukhtar etal., 2025; Coquand etal., 2024; Coquand etal., 2021), could beexpanded in the future. Moreover, genetic engineering used to label specific cell types and deliver genetic sequences on those cultures, or cell delivery approaches, should bebeneficial for future therapeutic approaches in humans invivo. To conclude, exvivo acute and organotypic human cultures provide beneficial approaches to understand human brain development, aging, evolution and disorders. They could provide patient-oriented therapeutical medicine, in particular for drug-resistant disorders. That is to say, the emergence of such models requires standards adopted by the community, in terms of experimental protocols (tissue transportation, cutting inhibitors, culture medium), quality assessments (electrophysiology, morphology, culture infections), metadata management (age, sex, origin, sociocultural status, IQ, etc.) and ethical standards (communication, consent approval & post-mortem donations in particular in children and intellectual deficiency conditions, genomic experiments). Another key aspect is to improve the communication between basic research, clinicians, patient involvement and companies to facilitate tissue sharing, explorative research and drug development. Moreover, preclinical drug development, whatever the preclinical model (exvivo, invitro, animal) requires strong relevance of the outcome and parameters assessed related to what is expected in human individuals (e.g., blood–brain barrier penetration, pharmacokinetics and dynamics, toxicity, dose selection, biomarkers, end points), to ensure higher chance of translation. Discussion: singularity, specificity, and experimental approaches In this essay, Ihave explored multiple layers of divergence in the human lineage, from early neurodevelopment to neuronal properties and neurocognitive features. None of these differences are strictly “human-specific,” consistent with Darwin’s view that most differences between humans and other animals are “of degree, not of kind” (Richerson etal., 2021; Lindhout etal., 2024; Darwin, 1871). Therefore, Iadvocate for the concept of “species-singularity” or “human speciesspecificity” rather than claiming human uniqueness. The specificity of human neurodevelopment results from a complex interplay of evolutionary cellular mechanisms that influence brain cytoarchitecture, connectivity, neuronal properties, and circuit function, culminating with enhanced cognitive abilities, in a cultural species (Pollen etal., 2023). The molecular mechanisms underlying these processes are human-specific evolutionary innovations combined with hominid-, primate-, mammalian-, vertebrate-, and metazoan-conserved mechanisms (Lancaster, 2024; Tosches, 2021). Human modifiers modulate, refine or combine ancestral mechanisms in an “evolutionary tinkering” (Jacob, 1977). Libé-Philippot 10.3389/fnsyn.2025.1672646 Frontiers in Synaptic Neuroscience 08 frontiersin.org In conclusion, while the meaning behind the stencils of human hands remains beyond our reach, experimental biology enables us to begin understanding the biological substrates of human neural evolution and of species-specific sensitivities to neurodevelopmental and neurological disorders. Complementary multimodal and multiscale approaches are beneficial to assess specificities of human neural properties, from the molecule to the behavioral levels, which could lead in the future to the discovery of novel therapeutic approaches based on human-specific cellular and molecular properties. Author contributions BL-P: Writing– original draft, Writing– review & editing. Funding The author declares that financial support was received for the research and/or publication of this article. BL-P research team is supported by the European Research Council (ERC, “hCerebEvol” project), the A*MIDEX Foundation (Marseille, France), the French CNRS agency and the French ATIP-Avenir program. Acknowledgments I thank members of the IBDM and “Human neuronal evolution” research team for scientific discussions, as well as the CBD and Vanderhaeghen research team (CBD VIB– KU Leuven, Belgium) for scientific contributions and discussions. Figures have been generated using Biorender. Conflict of interest BL-P is an inventor on a PCT application related to the work on LRRC37B. Generative AI statement The author declares that no Gen AI was used in the creation of this manuscript. Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If youidentify any issues, please contact us. 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