F on ie s in Synap ic Neu oscience 01 on ie sin.o g
Explo ing he singula i y o
human neu ons: keep calm and
ca y on
Bap is eLibé-Philippo *
Aix-Ma seille Uni e si é, CNRS, De elopmen al Biology Ins i u e o Ma seille (IBDM), Neu oMa seille,
Ma seille, F ance
The human b ain’s inc eased cogni i e abili ies a e unde pinned by e olu iona y
adap a ions a he molecula , cellula , and ci cui le els o neu al s uc u es. This
pe spec i e explo es how p o ac ed neu onal de elopmen and di e gen cell
in insic neu onal p ope ies, including neu onal exci abili y, con ibu e o human
neu obiological singula i y. Those cellula aspec s ely on molecula e olu iona y
inno a ions, including e olu ion o gene egula ion and gene duplica ions
ha play c i ical oles in p olonging synap ogenesis and educing neu onal
exci abili y. These molecula e olu iona y inno a ions a e shown o in e ac wi h
co e neu ode elopmen al molecula pa hways linked o neu ode elopmen al
diso de s. Fu he mo e, complemen a y mul imodal and mul iscale app oaches
o e p omising pla o ms o s udy hese p ocesses and de elop species- ele an
he apeu ic s a egies. They include ex i o acu e b ain slices and o gano ypic
cul u es which o e eme ging ools o unde s anding human species-speci ici ies
and neu al diso de s.
KEYWORDS
human b ain e olu ion, neu onal de elopmen and ma u a ion, human gene
duplica es, synap ic neo eny, neu onal exci abili y, ce eb al co ex, ex i o b ain
sec ions, neu ode elopmen al diso de s
In oduc ion
Nea my labo a o y, loca ed in he Calanques o Ma seille (F ance), lies he unde wa e
Cosque Ca e. Wi hin i s subme ged dep hs, p ehis o ic pain ings c ea ed be ween 27,000 and
14,000BC p o ide a s iking glimpse in o he dis an pas o Homo sapiens. The a wo k
depic s a ious animals—ho ses, ibex, dee , bison, au ochs, seals, and penguins—as well as
human symbols, including geni al ep esen a ions and s encils o human hands (Clo es e al.,
1992). While he p ecise meaning o hese an h opological signs emains elusi e, hey
undoub edly ep esen he cogni i e and cul u al e olu ion ha dis inguishes Homo sapiens
om o he p ima e, hominid and a chaic hominin species. No ably, hese ea u es, including
abs ac hinking, cul u al ansmission, social lea ning, coope a ion, and language (Riche son
e al., 2021; She wood and Gómez-Robles, 2017; Lancas e , 2024; Zebe g e al., 2024), a e
unde pinned by neu obiological subs a es ha e ol ed alongside mo phological, me abolic,
and immune sys em changes (Zebe g e al., 2024; Pollen e al., 2023).
Wha is he biological subs a e esponsible o such e olu iona y ad ancemen s? O e
he pas ou decades, esea ch has poin ed o he inc eased size o he human b ain,
pa icula ly he ce eb al co ex— he ou e mos laye o he b ain in ol ed in senso y
p ocessing and highe cogni i e unc ions—as a cen al elemen in he e olu ion o human
cogni ion (Figu e1A). This expansion has been associa ed wi h a la ge numbe o neu ons
and mo e complex cy oa chi ec u e wi hin he ce eb al co ex, which oge he con ibu e o
he inc eased cogni i e abili ies o humans. These changes p ima ily esul om he e olu ion
OPEN ACCESS
EDITED BY
Vik o Szegedi,
Hunga ian Cen e o Excellence o Molecula
Medicine (HCEMM), Hunga y
REVIEWED BY
Ikuo K. Suzuki,
The Uni e si y o Tokyo, Japan
*CORRESPONDENCE
Bap is e Libé-Philippo
[email p o ec ed]
RECEIVED 24 July 2025
ACCEPTED 28 Augus 2025
PUBLISHED
CITATION
Libé-Philippo B (2025) Explo ing he
singula i y o human neu ons: keep calm and
ca y on.
F on . Synap ic Neu osci. 17:1672646.
doi: 10.3389/ nsyn.2025.1672646
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(CC BY). The use, dis ibu ion o ep oduc ion
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which does no comply wi h hese e ms.
TYPE Mini Re iew
PUBLISHED
DOI 10.3389/ nsyn.2025.1672646
02 Oc obe 2025
02 Oc obe 2025
Libé-Philippo 10.3389/ nsyn.2025.1672646
F on ie s in Synap ic Neu oscience 02 on ie sin.o g
o neu ode elopmen al p ocesses, especially hose go e ning neu al
p oli e a ion, neu ogenesis, and a e de e mina ion du ing he
p ena al pe iod (She wood and Gómez-Robles, 2017; Lancas e , 2024;
Libé-Philippo and Vande haeghen, 2021; Lindhou e  al., 2024;
Vande haeghen and Polleux, 2023; Kelley and Pașca, 2022; Namba
and Hu ne , 2024).
Howe e , despi e signi ican ad ances in ou unde s anding o
hese de elopmen al p ocesses, ela i ely li le is known abou he
e olu ion o he undamen al building blocks o he b ain— he
neu ons hemsel es—and he ci cui s hey o m (Lancas e , 2024;
Vande haeghen and Polleux, 2023; Libé-Philippo e  al., 2024).
Humans sha e mos co ical neu on ypes wi h o he mammalian and
p ima e species, ye hese neu ons exhibi mo phological and
physiological di e ences ha may be cen al o he e olu ion o
human cogni ion. These di e ences a e hough o be linked o
species-speci ic gene exp ession pa e ns and human-speci ic
modi ie s o ances al molecula mechanisms, including pa hological
ones (Lancas e , 2024; Pollen e al., 2023; Vande haeghen and Polleux,
2023; Libé-Philippo e al., 2024; Wallace and Pollen, 2024).
Ca y on slowly: p o ac ed
synap ogenesis and enhanced
lea ning abili ies
A pa icula ly s iking ea u e o human neu ode elopmen is he
p o ac ed pace o neu onal de elopmen . This phenomenon, known
as he e och ony, b adych ony, o neo eny, e e s o he delayed
ma u a ion o key neu ode elopmen al p ocesses, including
co icogenesis and synap ic ma u a ion, in humans compa ed o o he
p ima e species (She wood and Gómez-Robles, 2017; Lancas e , 2024;
Libé-Philippo and Vande haeghen, 2021; Lindhou e  al., 2024;
Pe anjek e al., 2011; Zhou e al., 2024; McNama a, 2012). No ably,
neo eny o he synap ogenesis— he p ocess h ough which neu ons
o m connec ions in a highly plas ic manne (She wood and Gómez-
Robles, 2017; Wai es e al., 2005)—is hough o be he ounda ion o
he enhanced lea ning abili ies cha ac e is ic o Homo sapiens (Gould,
1992; Bu ill e al., 2011). Each s ep o his p o ac ed neu ode elopmen
could ollow di e en modali ies o he e och ony, in luenced by
a ious mechanisms, including epigene ic egula ion, me abolic
p ocesses, p o ein a ge ing o synapses, and human-speci ic modi ie s
ha egula e hese p ocesses (Libé-Philippo and Vande haeghen,
2021; Casimi e al., 2024; Cice i and S ude , 2024). Fo example,
synap ogenesis akes app oxima ely 5–10 yea s in humans, compa ed
o mon hs in macaques and weeks in mice, while co icogenesis las s
mon hs in humans, as opposed o weeks in macaques and days in mice
(Libé-Philippo and Vande haeghen, 2021; Lindhou e al., 2024; Libé-
Philippo e al., 2024). Fu he mo e, i is concei able ha di e en
b ain egions unde go a ying a es o de elopmen al ma u a ion,
wi h synap ogenesis showing mo e p onounced he e och onici y in
a eas such as he p e on al co ex— egion associa ed wi h highe
cogni i e unc ions (Pe anjek e al., 2011)—compa ed o p ima y
senso y and mo o a eas (She wood and Gómez-Robles, 2017).
Unde s anding he molecula and cellula subs a es unde lying
his p o ac ed neu ode elopmen is pi o al o unco e ing he
dis inc i e cogni i e abili ies o humans. I is also c i ical o
unde s anding undamen al bases o neu ode elopmen al diso de s
since hey may bein ima ely linked o dis u bed pace o synapse
de elopmen , in pa icula in au ism spec um diso de and
schizoph enia (Penzes e al., 2011). P e ious s udies ha e shown ha
neu ons de i ed om human, chimpanzee and mouse plu ipo en
s em cells and xeno ansplan ed in o mouse ce eb al co ex, ma u e a
hei own pace (Libé-Philippo and Vande haeghen, 2021;
Vande haeghen and Polleux, 2023; Lina o e  al., 2019; Espuny-
Camacho e al., 2013; Ma che o e al., 2019; Gaspa d e al., 2008). This
sugges s ha he pace o neu onal de elopmen is p ima ily d i en by
cell-in insic, species-speci ic mechanisms, included a he synap ic
ma u a ion le el (Libé-Philippo e al., 2024).
Wha molecula mechanisms unde pin hese changes in he pace
o de elopmen ? Many o he de elopmen al p ocesses, cell ypes, and
gene exp ession pa e ns in ol ed in neu ode elopmen a e highly
conse ed ac oss e eb a e species, wi h basic neu onal and synap ic
unc ions sha ed e en among dis an me azoan axa (Lancas e , 2024;
Libé-Philippo and Vande haeghen, 2021; Zhou e al., 2024; Tosches,
2021). Howe e , many o he genomic inno a ions speci ic o he
human lineage a e linked o neu ode elopmen al and neu onal
physiological p ocesses. On examples a e mu a ions in cis- egula o y
elemen s ha ep esen abou 1% o he genomic di e ences be ween
Homo sapiens and chimpanzees and ha esul in no el gene
exp ession pa e ns (Pollen e  al., 2023; Libé-Philippo and
Vande haeghen, 2021; Lindhou e al., 2024; Vande haeghen and
Polleux, 2023; Kelley and Pașca, 2022; Libé-Philippo e al., 2024;
Zhou e al., 2024; Whalen and Polla d, 2022; King and Wilson, 1975).
This includes human gain enhance s in he mo e han 3,000 human
accele a ed egions, which a e la gely non-coding egula o y genomic
egions, highly conse ed be ween mammalian species bu di e gen
in he human genome, ha a e pa icula ly ac i e in neu al p ocesses
(Pollen e  al., 2023; Libé-Philippo and Vande haeghen, 2021;
Lindhou e al., 2024; Vande haeghen and Polleux, 2023; Kelley and
Pașca, 2022; Libé-Philippo e al., 2024; Zhou e al., 2024).
These egula o y changes can lead o species-speci ic di e en ial
pa e ns o gene exp ession. Fo ins ance, OSTN (os eoc in) is a muscle
and bone sec e ed p o ein bu exp essed in he b ain only in p ima e
species. I egula es he p o ac ed ma u a ion o he dend i ic ee
(A aman e al., 2016). This could beexplained by he p esence in he
genomes o p ima e species o binding si es o he ansc ip ion ac o s
o he MEF2 amily, in ol ed in synap ic ma u a ion (A aman e al.,
2016). In e es ingly, MEF2A was iden i ied o display a p o ac ed
de elopmen al exp ession pa e n in he human ce eb al co ex
compa ed o o he p ima e species (Liu e  al., 2012). S iking
expe imen al wo ks e ealed human-speci ic dele ions in
cis- egula o y elemen s o CBLN2 (ce ebellin 2), and highe e inoic
acid signaling in he p ima e p e on al co ex, which led o CBLN2
highe le els o exp ession leading o inc ease synapse o ma ion and
co ical connec i i y (Shiba a e al., 2021; Shiba a e al., 2021).
Ano he le el o molecula e olu iona y no el ies elies on
segmen al gene duplica ions, such as species-speci ic gene duplica es
(Pollen e  al., 2023; Libé-Philippo and Vande haeghen, 2021;
Lindhou e al., 2024; Vande haeghen and Polleux, 2023; Kelley and
Pașca, 2022; Libé-Philippo e al., 2024; Zhou e al., 2024; Bailey e al.,
2002; So o e al., 2025). One well-documen ed example o such a
genomic inno a ion is he SRGAP2 (SLIT-ROBO Rho GTPase
Ac i a ing P o ein 2) gene amily, speci ically he human-speci ic
SRGAP2B and SRGAP2C genes. These genes, which a ose du ing he
eme gence o Homo species, ha e been shown o induce p o ac ed
synap ic ma u a ion and enhanced neu onal connec i i y when
Libé-Philippo 10.3389/ nsyn.2025.1672646
F on ie s in Synap ic Neu oscience 03 on ie sin.o g
o e exp essed in mouse co ical neu ons, leading o enhanced co ical
connec i i y and lea ning abili ies (Lancas e , 2024; Pollen e al., 2023;
Libé-Philippo and Vande haeghen, 2021; Vande haeghen and
Polleux, 2023; Kelley and Pașca, 2022; Namba and Hu ne , 2024;
Cha ie e al., 2012; Schmid e al., 2021). I was ecen ly con i med
ha SRGAP2B and SRGAP2C a e essen ial o p o ac ed synap ic
ma u a ion, as demons a ed by he knockdown o hei exp ession in
human co ical neu ons xeno ansplan ed in o he mouse ce eb al
co ex (Figu e1C) (Libé-Philippo e al., 2024). Su p isingly, hese
expe imen s e ealed ha he accele a ion o synap ic de elopmen
was mo e p onounced han expec ed: a 18 mon hs pos -
ansplan a ion, he neu ons had eached synap ic densi ies simila o
hose obse ed in 5–10-yea -old child en.
Fu he mo e, he expe imen s unco e ed a no el molecula
mechanism in ol ing a compe i ion be ween he synap ic p o eins
SRGAP2A and SYNGAP1 (Synap ic Ras GTPase-ac i a ing p o ein
1), which egula e he iming o synap ogenesis in mammals, wi h
SRGAP2B and SRGAP2C ac ing as human-speci ic modi ie s (Libé-
Philippo e al., 2024). SYNGAP1 is a majo gene esponsible o
in ellec ual disabili y and au ism spec um diso de (Gamache e al.,
2020). One cellula pheno ype o SYNGAP1 haploinsu iciency is a
p ecocious synap ic de elopmen o dis up ed neo eny (Ve mae cke
e al., 2024), as obse ed in some o ms on au ism spec um diso de
(Penzes e al., 2011). In e es ingly, SYNGAP1 pos synap ic synap ic
accumula ion and he pheno ype o accele a ed synap ogenesis could
be escued while pe o ming SRGAP2A knock-down in a SYNGAP1
haploinsu iciency gene ic backg ound (Libé-Philippo e al., 2024),
opening possibili ies o u u e he apeu ic app oaches (Figu e1C).
Those ecen s udies highligh se e al le els o b eaks ha ac on
he p o ac ion o he synap ic de elopmen . While he e olu ion o
gene egula ion (e.g., epigene ics, non-coding genomic egions) ac s
on di e ences in he pa e n and pace a he ansc ip ion s ep (Pollen
e al., 2023; Libé-Philippo and Vande haeghen, 2021; Lindhou e al.,
2024; Vande haeghen and Polleux, 2023; Kelley and Pașca, 2022; Libé-
Philippo e al., 2024; Zhou e al., 2024; Cice i and S ude , 2024;
A aman e al., 2016; Liu e al., 2012; Shiba a e al., 2021; Shiba a e al.,
2021), and a e easily assessed by ansc ip omic s udies, addi ional
non-gene ic pos - ansc ip ional b eaks ac on he p o ein abundance
a he synapse. Indeed, he de elopmen al pace o a ia ion in he
synap ic abundance o some p o eins does no i wi h he a ia ion o
he ansc ip s, sugges ing pos - ansc ip ional and/o ansla ional
and/o p o ein s abili y egula ion (Wang e al., 2023). Such egula ion,
in ol es he ac i i y o small GTPases ha could media e synapse
a ge ing (Wang e al., 2023) o he in e ac ion be ween human-
speci ic p o eins wi h hei ances o s ha can lead o hei deg ada ion
(Libé-Philippo e al., 2024; Assendo p e al., 2024). This indica es ha
u u e s udies on (local) ansla ion, p o ein s abili y, p o ein
co- a icking and cell-s a e dependan synap ic a ge ing, beyond
FIGURE1
Human modi ie s o neu onal de elopmen and physiology modula e neu onal disease pa hways. (A) E olu ion o he b ain size. (B) Species-speci ic
neu onal ea u es. (C) Human-speci ic modi ie s o synapse de elopmen and o neu ode elopmen al diso de molecula pa hway. (D) Human
modi ie o neu onal exci abili y and o neu ological diso de molecula pa hway.
Libé-Philippo 10.3389/ nsyn.2025.1672646
F on ie s in Synap ic Neu oscience 04 on ie sin.o g
c oss-species ansc ip ional compa isons, could bebene icial o a
deepe unde s anding on he e olu ion o synap ic de elopmen
and s uc u e.
One could wonde why se e al le els o mechanisms o b eaks
e ol ed in he same di ec ion, e.g., a p o ac ed neu onal and synap ic
ma u a ion. On one hand, his could ensu e he obus ness (Hiesinge
and Hassan, 2018) o his key human de elopmen al ea u e. On he
o he hand, a s ong obus ness o excessi e a ia ions, e.g., neo enic
dis up ion, allows sub le a ia ions (Hiesinge and Hassan, 2018). One
could ex apola e ha di e en scales o sub le a ia ions could bekey
in he de elopmen o human ci cui s: (1) a ia ions be ween neu ons/
synapses ha may bec ucial o achie e de elopmen al obus ness
(Hiesinge and Hassan, 2018), (2) i could bein ol ed in di e en
paces o de elopmen be ween neu onal compa men s (e.g.,
dissocia e he pace o de elopmen o synapse sub ypes, synapses
e sus axon, dend i es, e c.), o (3) be ween ce eb al co ex a ea (e.g.,
a highe p o ac ion in he p e on al co ex e sus mo o co ex).
Mo eo e , one could imagine ha such p o usion o b eaks could ha e
pa icipa ed in he e ol abili y o Homo species.
Keep calm: educed neu onal
exci abili y and enhanced
compu a ional p ope ies
While much a en ion has been paid o he de elopmen al aspec s
o human neu onal e olu ion, less is known abou he species-speci ic
physiological cha ac e is ics o human co ical neu ons and he
unde lying mechanisms ha gi e ise o hese ai s (Vande haeghen
and Polleux, 2023; Libé-Philippo e  al., 2024). C oss-species
compa isons om ex i o b ain sec ions, o igina ing om
non-pa hological su gical esec ions p o ided human speci ici ies a
he mo phological, physiological and connec i i y le els, in he
ce eb al co ex (py amidal exci a o y neu ons and GABAe gic
in e neu ons), in he hippocampus (connec i i y) and in he
ce ebellum (Pu kinje cells) (Libé-Philippo e al., 2023; Beaulieu-
La oche e al., 2021; Beaulieu-La oche e al., 2018; Kalmbach e al.,
2018; Wilson e al., 2025; Wa son e al., 2025; Mohan e al., 2015; Eyal
e al., 2014; Dei che e al., 2017; Hun e al., 2023; Cha and e al.,
2023; Busch and Hansel, 2023; Masoli e al., 2024; Campagnola e al.,
2022; Szegedi e al., 2020; Molná e al., 2016; Wilson e al., 2025; Oláh
e al., 2025; Cseme e al., 2023; Kalmbach e al., 2021; Wilbe s e al.,
2023), sugges ing co-e olu ion o b ain egions, o which emains he
ques ion o he unde lying mechanisms (common molecula
inno a ions, adap a ion, e c.). Mo phologically, human neu ons a e
la ge , exhibi ing mo e elabo a e dend i ic a bo iza ion and a g ea e
numbe o synapses leading o highe neu al connec i i y compa ed
o o he p ima es. These ea u es a e hough o con ibu e o he
enhanced compu a ional p ope ies o human neu ons
(Vande haeghen and Polleux, 2023; Libé-Philippo e al., 2024). A he
elec ophysiological le el, human neu ons a e mo e
compa men alized, less exci able, and capable o gene a ing long
ains o ac ion po en ials when engaged in cogni i e asks, compa ed
o neu ons in o he mammals and p ima es (Figu e 1B)
(Vande haeghen and Polleux, 2023; Libé-Philippo e al., 2024). Fine
uning o in insic neu onal exci abili y is c i ical since dis u bed
in insic neu onal exci abili y is in ima ely linked o neu ological
diso de s, including epilepsy, mig aine and neu odegene a i e
diso de s (Wijesinghe and Camp, 2011). Mo e a en ion will
bep obably paid in he coming yea s a he scales beyond neu onal
p ope ies, o ins ance ci cui s uc u e and compu a ional p ope ies.
Those di e gen cellula ea u es should ely on molecula
no el ies, including di e gence in cis- egula o y elemen s, e en
hough a comp ehensi e molecula subs a e o hose e olu iona y
di e gen ea u es is a o beunde s ood. These changes can lead o
di e en ial pa e ns o gene exp ession. Fo ins ance genes
di e en ially exp essed in human co ical py amidal neu ons
compa ed o o he p ima e and hominid species a e no ably linked o
synap ic compa men s’ s uc u e and physiology (Jo s ad e al., 2023).
Mo eo e , among human duplica ed genes, FRMPD2B and LRRC37B
should play a c i ical ole in he di e gence o human neu ons,
FRMPD2B in synap ic signaling (So o e al., 2025) and LRRC37B in
neu onal exci abili y (Libé-Philippo e al., 2023).
I was ecen ly shown ha human co ical neu ons exhibi g ea e
di e si y in he exci abili y o hei axon ini ial segmen (AIS), he
subcellula compa men whe e ac ion po en ials a e ini ia ed (Libé-
Philippo e al., 2023). The consequence a he ci cui and in o ma ion
p ocessing le els emains o beexplo ed. This lowe exci abili y could
be an adap i e esponse o he inc eased neu al connec i i y in
humans, esul ing in highe accu acy o in o ma ion p ocessing. This
could con ibu e o allowing o sus ained ains o ac ion po en ials
du ing cogni i e asks wi hou comp omising signal ideli y. This
al e ed exci abili y may also modula e in o ma ion p ocessing a bo h
he neu onal and ci cui le els by in luencing neu onal gain and
inc easing neu onal di e si y (Libé-Philippo e al., 2024).
A pi o al disco e y was he iden i ica ion o he hominid-speci ic
ansmemb ane p o ein LRRC37B (Leucine Rich Repea Con aining
37B), which is localized o he AIS o a subse o human co ical
neu ons. S ikingly, LRRC37B was ound o educe neu onal
exci abili y a he le el o he AIS (Libé-Philippo e  al., 2023).
In e es ingly, humans possess mo e han 15 pa alogs o he LRRC37
gene amily, which encodes ansmemb ane p o eins wi h leucine- ich
ex acellula domains. Among hese pa alogs, LRRC37B is speci ic o
humans and hominids (including chimpanzees), di e ing om he
o he pa alogs and he ances al L c37a ound in o he amnio es
(Libé-Philippo e al., 2023; Giannuzzi e al., 2013). The ances al
L c37a gene is no exp essed in he mouse ce eb al co ex and
LRRC37B ansc ip is exp essed a highe le els in human co ical
py amidal neu ons han in chimpanzees (Libé-Philippo e al., 2023).
Mo eo e , he LRRC37B p o ein is no de ec ed a he AIS o he
chimpanzee co ical py amidal neu ons (Figu e1D) (Libé-Philippo
e al., 2023).
The AIS, a c ucial si e en iched wi h ol age-ga ed sodium
channels (Na
), which a e essen ial o ac ion po en ial gene a ion
(Libé-Philippo e al., 2023). Using a ious expe imen al app oaches,
i was demons a ed ha LRRC37B in e ac s wi h wo key modula o s
o Na
channels—sec e ed FGF13 ( ib oblas g ow h ac o 13)
iso o m A (FGF13A) and he ansmemb ane p o ein SCN1B
(β-subuni o Na )— o modula e neu onal exci abili y (Libé-Philippo
e al., 2023). Ex i o elec ophysiological eco dings showed ha
LRRC37B o e exp ession in mouse co ical py amidal neu ons
enhances he inhibi o y e ec o FGF13A on Na
channels, hus
dec easing neu onal exci abili y a he AIS (Figu e1D) (Libé-Philippo
e al., 2023). One could imagine ha explo ing how o modula e he
LRRC37B–FGF13A–SCN8A in e ac ion o ac on neu onal
exci abili y, could beuse ul o cu e epilep ic diso de s.
Libé-Philippo 10.3389/ nsyn.2025.1672646
F on ie s in Synap ic Neu oscience 05 on ie sin.o g
The e o e, LRRC37B is a human species-speci ic modula o o AIS
and neu onal exci abili y and i ac s by concen a ing FGF13A
unc ion on Na
channels (Figu e1D) (Libé-Philippo e al., 2024;
Libé-Philippo e al., 2023). This wo k opens an a enue o add ess
many ques ions in he u u e, including he consequences o a di e se
lowe exci abili y o he AIS o he neu al ci cui unc ion and
in o ma ion p ocessing.
Ano he aspec ha his s udy highligh is he he e ogenei y in he
p o ein composi ion o a neu onal compa men , i.e., a subpopula ion
o any neu onal sub ype exp ess LRRC37B p o ein a hei AIS (Libé-
Philippo e al., 2023), be ween co ical neu ons. This ollows o he
s udies showing a highe di e si y o specializa ion o neu ons in he
human ce eb al co ex compa ed o o he species (Jo s ad e al., 2023;
Be g e al., 2021). This challenges he de ini ion o neu onal ype
de ined by ansc ip ma ke exp ession, as ecen ly done in he
zeb a ish in which ansc ip ionally simila neu ons can
be unc ionally di e se (Shaine e al., 2025). One could wonde which
ansc ip ional and pos - ansc ip ional mechanisms e ol ed in
humans leading o po en ial highe molecula di e si y wi hin
neu onal popula ions. This can in ol e o ins ance cell-s a e
dependen mechanisms, ansla ional o sub-compa men p o ein
a ge ing mechanisms, mo phological/synap ic inne a ion
dependen mechanisms, o bes udied u he . Rega ding he po en ial
impac o such highe di e si y o specializa ion, one could wonde
whe he his led o changes in neu al p ocessing, including he
eliabili y and obus ness o neu al in o ma ion p ocessing, unc ional
specializa ion, complexi y o neu onal in o ma ion ansmission,
obus lea ning (Wu e al., 2025; Pe ez-Nie es e al., 2021; Gjo gjie a
e al., 2016). No el expe imen al models and compu a ional biology
should help in he nea u u e o elucida e which o hose unc ional
p ope ies could ha e eme ged om he human neu onal e olu ion,
beyond expanded co ical size.
Species-speci ic sensi i i ies o
neu ode elopmen al and b ain
diso de s
In e es ingly, many o he cellula p ocesses in ol ed in human
neu al e olu ion and he genes ha dis inguish he human lineage a e
closely ied o neu ode elopmen al diso de s, aging, and b ain
diseases (Libé-Philippo and Vande haeghen, 2021; Zhou e al., 2024;
Vicke y e al., 2024; Douaud e al., 2014). Fo ins ance, dys egula ion
o neu ode elopmen al p ocesses, such as hose occu ing du ing
neu al p oli e a ion and ha e ol ed in humans, can lead o de ec s in
he inal b ain cy oa chi ec u e, esul ing in condi ions such as
mic ocephaly and mac ocephaly (Libé-Philippo and Vande haeghen,
2021). Mu a ions in human accele a ed egions, while di e gen o all
o he mammalian species, a e en iched in indi iduals wi h
neu ode elopmen al diso de s and unde lie o ins ance 5% o
consanguineous cases o au ism spec um diso de s (Doan e al.,
2016). Fo ins ance, MEF2 genes and hei binding si es a e linked o
au ism spec um diso de (Chaudha y e al., 2021). Some o he genes
displaying human species-speci ic de elopmen al pa e ns o
exp ession like CBLN2 code o p o eins ha a e ligands o ecep o s
igh ly linked o neu ode elopmen al diso de s (e.g., neu exins)
(Südho , 2023), sugges ing ha hey could media e species-speci ic
sensi i i ies o hose diso de s.
Some human duplica ed genes eside in genomic ho spo s linked
o neu ode elopmen al diso de s, including au ism spec um diso de
(So o e  al., 2025). O he human duplica ed genes, and no ably
SRGAP2C and LRRC37B, a e loss-o - unc ion in ole an , sugges ing
s ong le els o pu i ying selec ion (So o e al., 2025). They could ac
as species-speci ic modi ie s o molecula pa hways implica ed in
neu ode elopmen al diso de s (Libé-Philippo e al., 2024; Assendo p
e al., 2024). Speci ically, he SRGAP2 gene amily, and pa icula ly he
human-speci ic genes SRGAP2B and SRGAP2C, we e unc ionally
linked o SYNGAP1 and CTNND2, wo synap ic p o eins associa ed
wi h in ellec ual disabili ies, au ism spec um diso de s, and C i-du-
Cha synd ome (Libé-Philippo e al., 2024; Assendo p e al., 2024).
Addi ionally, he hominid-speci ic p o ein LRRC37B was
demons a ed o in e ac wi h FGF13A, SCN1B and SCN8A ha a e
in ol ed in epilepsy, D a e synd ome, and au ism spec um diso de
(Libé-Philippo e al., 2023). These esul s highligh he possibili y o
species-speci ic sensi i i ies o neu ode elopmen al and neu ological
diso de s ha ha can bec i ical in he diagnosis, pa ien managemen
and he apeu ical app oaches.
In ou knowledge, neu ode elopmen al diso de s like au ism
spec um and schizoph enia ha e no been desc ibed in nonhuman
p ima es, e en hough common gene ic and social beha io al ai s
ha e been iden i ied compa ed o o he species, including
chimpanzees (Li e al., 2021; Faughn e al., 2015; Yoshida e al., 2016;
C ow, 1997). I would mean ha such diso de s a e he consequence
o genomic ade-o s be ween neu al ci cui e olu ion and ha m ul
e ec s in he a ia ion o hei de elopmen and s uc u e (Sikela and
Sea les Quick, 2018). This appa en e olu ion o ulne abili y o
neu ode elopmen al diso de s could esul om human species-
speci ic causes o such diso de s (e.g., gene ic e olu ion and p o ac ed
de elopmen ), na u al selec ion in nonhuman species agains such
a ia ions, o on he ac ha he de ini ion o such diso de s a e based
on beha io al ai s expanded in humans (e.g., language). Mo eo e ,
humans display species-speci ic g ay ma e decline linked o aging in
ce eb al co ex a ea ha di e ged in size compa ed o chimpanzees
(no ably, he p e on al and on al ce eb al co ex) (Vicke y e al.,
2024). While se e al animal species, including non-human p ima es,
display age- ela ed amyloid-β and au accumula ion, he e is deba e
on whe he cellula loss and beha io al diso de s linked o Alzheime ’s
disease migh bea human-speci ic diso de (De insky e al., 2018;
Finch and Aus ad, 2015).
Human ex i o app oaches o basic
esea ch and d ug de elopmen
How s udying human b ain basic de elopmen , unc ion, and
diso de s? Answe ing his ques ion necessi a es mul imodal and
mul iscale app oaches. Indeed, depending on he scale o he s udy,
om genes o cell o ci cui o beha io , one could conside human
indi iduals hemsel es, p ima y samples, human plu ipo en s em
cell-based models (2D di e en ia ions, o ganoids, assembloids) o
animal expe imen a ion (Figu e2). These app oaches di e no only
on he accessible scales bu also on he s ages and neu al p ocesses
hey can add ess. Mo eo e , e e y biological echnology and app oach
canno beaccessible by each o hose app oaches on i s own.
In his con ex , spa e human b ain issues ob ained om
neu osu gical p ocedu es can beused in acu e condi ions o add ess

Libé-Philippo 10.3389/ nsyn.2025.1672646
F on ie s in Synap ic Neu oscience 06 on ie sin.o g
cellula p ope ies, mo phologies, “omic” (genomic, epigene ic,
ansc ip omic, p o eomic, me abolomic, lipidomic, e c.) and
molecula ques ions (Libé-Philippo e al., 2023; Beaulieu-La oche
e al., 2021; Beaulieu-La oche e al., 2018; Kalmbach e al., 2018;
Wilson e al., 2025; Wa son e al., 2025; Mohan e al., 2015; Eyal e al.,
2014; Dei che e al., 2017; Hun e al., 2023; Cha and e al., 2023;
Busch and Hansel, 2023; Masoli e al., 2024; Campagnola e al., 2022;
Szegedi e al., 2020; Molná e al., 2016; Wilson e al., 2025; Oláh e al.,
2025; Cseme e al., 2023; Kalmbach e al., 2021; Wilbe s e al., 2023;
Wilbe s e al., 2023; Ke kho s e al., 2018; Wie da e al., 2024; Lee e al.,
2023; Kim e al., 2023; Be na d e al., 2004; Buchin e al., 2022; Ting
e al., 2018; Gidon e al., 2020; Lee e al., 2023; Szegedi e al., 2024;
Bocchio e al., 2019; Szegedi e al., 2023; Szegedi e al., 2017; Yang
e al., 2025; Yang e al., 2024; Szegedi e al., 2016; Ba zó e al., 2025;
Gue -McC eigh e al., 2023; Rich e al., 2022; Me ens e al., 2024;
Mo adi Chameh e al., 2021; Go iouno a e al., 2018). In e es ingly,
neu onal physiology can becombined wi h pos -hoc mo phological
and connec i i y econs uc ions, p o ein immunos aining and
ansc ip omic app oaches. Such app oaches can beo in e es o
add ess ques ions on ma u e and aging issues because o he
p o ac ed neu onal de elopmen ha make o he human models’
imma u e, and on a gene ic and epigene ic human and aged
backg ound (Figu e 2). The sec ions come om co ical and
hippocampal egions, mos ly, and om d ug- esis an o cance
pa ien s. Impo an ly, esh au opsies could bean al e na i e sou ce o
issue, wi h con ol condi ions and o e ing mo e di e se b ain egions
(Ve we e al., 2002; Ve we e al., 2002; Plug e al., 2024). This enabled
o s udy non-pa hological egions (e.g., issues wi h no lesions
su ounding an epilep ic ocus o a umo ) (Libé-Philippo e al., 2023;
Beaulieu-La oche e al., 2021; Beaulieu-La oche e al., 2018; Kalmbach
e al., 2018; Wilson e al., 2025; Wa son e al., 2025; Mohan e al., 2015;
Eyal e al., 2014; Dei che e al., 2017; Hun e al., 2023; Cha and
e al., 2023; Busch and Hansel, 2023; Masoli e al., 2024; Campagnola
e al., 2022; Szegedi e al., 2020; Molná e al., 2016; Wilson e al., 2025;
Oláh e al., 2025; Cseme e al., 2023; Kalmbach e al., 2021; Wilbe s
e al., 2023; Wilbe s e al., 2023; Ke kho s e al., 2018; Wie da e al.,
2024; Lee e al., 2023; Kim e al., 2023; Ting e al., 2018; Gidon e al.,
2020; Lee e al., 2023; Szegedi e al., 2024; Bocchio e al., 2019; Szegedi
e al., 2023; Szegedi e al., 2017; Yang e al., 2025; Yang e al., 2024;
Szegedi e al., 2016; Ba zó e al., 2025; Gue -McC eigh e al., 2023;
Me ens e al., 2024; Mo adi Chameh e al., 2021; Go iouno a e al.,
2018), pa hological egions (e.g., epilep ic ocus) (Be na d e al., 2004;
Buchin e al., 2022; Rich e al., 2022) and c oss-species compa isons
(e.g., oden s e sus nonhuman p ima es e sus humans) (Libé-
Philippo e al., 2023; Beaulieu-La oche e al., 2021; Beaulieu-La oche
e al., 2018; Kalmbach e al., 2018; Wilson e al., 2025; Wa son e al.,
2025; Mohan e al., 2015; Eyal e al., 2014; Dei che e al., 2017; Hun
e al., 2023; Cha and e al., 2023; Busch and Hansel, 2023; Masoli
FIGURE2
Expe imen al models o s udy human b ain de elopmen , aging, diso de s and e olu ion. In g een accessible aspec s o he models, in o ange limi ed
access, in g een accessible aspec s.
Libé-Philippo 10.3389/ nsyn.2025.1672646
F on ie s in Synap ic Neu oscience 07 on ie sin.o g
e al., 2024; Campagnola e al., 2022; Szegedi e al., 2020; Molná e al.,
2016; Wilson e al., 2025; Oláh e  al., 2025; Cseme e  al., 2023;
Kalmbach e al., 2021; Wilbe s e al., 2023).
In e es ingly, hose acu e eco dings enable o assess he acu e
e ec o o ganic compounds (e.g., ca ein, ecep o agonis s/modula o
o channel blocke s) (Ke kho s e al., 2018; Bocchio e  al., 2019;
Szegedi e al., 2023; Yang e al., 2025; Yang e al., 2024), ideally in a
dose– esponse manne , on elec ophysiological p ope ies. This is o
pa icula in e es o d ugs ha a ge p o eins selec i ely exp essed
o highe exp essed in humans, like HCN channels (Kalmbach e al.,
2018; Szegedi e  al., 2023), o o con i ma ion o esul s go in
non-human animals (Yang e al., 2025).
Impo an ly, some s udies desc ibed e olu ion o
elec ophysiological p ope ies ac oss li e (Ba zó e al., 2025; Gue -
McC eigh e al., 2023). They iden i ied he age o he indi idual as a
c i ical pa ame e o changes wi h c i ical changes in mos o he
elec ophysiological pa ame e s in he i s yea o li e, o es ing
memb ane po en ial un il 40 yea s old and inpu esis ance changes
om his age (Ba zó e al., 2025), as well as inc ease in sag ampli ude
and dec ease in spike a e wi h age (50 yea s old) (Gue -McC eigh
e al., 2023), sugges ing ha ep oducibili y and clinical ansla ion o
d ug deli e y expe imen s needs o pay a en ion o hese 3 pe iods o
li e ( i s yea o li e, 1–40/50 yea s old, >40/50 yea s old). Mo eo e ,
some elec ophysiological p ope ies co ela es wi h IQ sco es
(Go iouno a e al., 2018), sugges ing ha o he me ada a should
beno ed while doing such expe imen s.
O gano ypic co ical sec ions we e success ully cul u ed o a
couple o weeks ex i o on a i icial o human ce eb ospinal luids
wi h s able neu onal mo phology and elec ophysiological p ope ies
(Ve we e al., 2002; Ve we e al., 2002; Plug e al., 2024; Schwa z
e al., 2019; O’Conno e al., 1997; Eugène e al., 2014; Ande sson e al.,
2016; Ting e al., 2018; Schwa z e al., 2017; McGeachan e al., 2025;
McGeachan e  al., 2025; Bak e  al., 2024; Wickham e  al., 2020;
Ande sson e al., 2016; Vo ms ein-Schneide e al., 2020; Chaichana
e al., 2007; Jung e al., 2002; Ra i e al., 2019; Mendes e al., 2018;
Sebollela e al., 2012; Ba h e al., 2021; Da Seixas Sil a e al., 2017; Da
Seixas Sil a e al., 2017; Ve we , 2003; Wu e al., 2008; Taylo e al.,
2024; Le Duigou e al., 2018; McLeod e al., 2023; And ews e al., 2020;
Sub amanian e al., 2017; Mukh a e al., 2025; Chen e al., 2023;
G aybuck e al., 2021; Ting e al., 2018; Schünemann e al., 2025). Such
app oaches enable o explo e basic and pa hological mechanisms in
human b ain issues om he molecula o he cell o he ci cui le els
(Figu e2). They open he possibili y o pe o m dynamic expe imen s
(e.g., li e imaging, calcium ac i i y, elec ophysiology) (Wickham
e al., 2020; Ande sson e al., 2016; Le Duigou e al., 2018; And ews
e al., 2020; Sub amanian e al., 2017; Mukh a e al., 2025) wi h
gene ic manipula ions (e.g., i al injec ion deli e y, op ogene ics)
(O’Conno e al., 1997; Eugène e al., 2014; Ande sson e al., 2016;
Ting e al., 2018; Ande sson e al., 2016; Vo ms ein-Schneide e al.,
2020; Le Duigou e al., 2018; McLeod e al., 2023; And ews e al., 2020;
Mukh a e al., 2025; G aybuck e al., 2021; Ting e al., 2018) o d ug
applica ions (e.g., dose– esponse) (Ra i e al., 2019; Mendes e al.,
2018; Taylo e al., 2024; And ews e al., 2020), as well as cell g a ing
(Wu e al., 2008), wi h con ol condi ions om he same indi idual.
They ha e mos ly been pe o med in adul condi ions,
non-pa hological (e.g., ou side an epilep ic ocus) (Ve we e al., 2002;
Ve we e al., 2002; Schwa z e al., 2019; Ande sson e al., 2016; Ting
e al., 2018; Schwa z e al., 2017; Bak e al., 2024; Wickham e al., 2020;
Ande sson e al., 2016; Le Duigou e al., 2018; Chen e al., 2023;
G aybuck e al., 2021; Ting e al., 2018; Schünemann e al., 2025) and
pa hological (e.g., epilepsy, umo en i onmen , neu odegene a i e
condi ions) (Schwa z e al., 2019; O’Conno e al., 1997; Eugène e al.,
2014; McGeachan e al., 2025; McGeachan e al., 2025; Vo ms ein-
Schneide e al., 2020; Chaichana e al., 2007; Jung e al., 2002; Ra i
e al., 2019; Mendes e al., 2018; Sebollela e al., 2012; Ba h e al., 2021;
Da Seixas Sil a e al., 2017; Da Seixas Sil a e al., 2017; Ve we , 2003;
Wu e al., 2008; Taylo e al., 2024; Plug e al., 2024) wi h d ugs o i al
applica ions (Plug e al., 2024), bu explo ing neu ode elopmen al
s ages (McLeod e al., 2023), including e al s ages (McLeod e al.,
2023; And ews e al., 2020; Sub amanian e al., 2017; Mukh a e al.,
2025; Coquand e al., 2024; Coquand e al., 2021), could beexpanded
in he u u e. Mo eo e , gene ic enginee ing used o label speci ic cell
ypes and deli e gene ic sequences on hose cul u es, o cell deli e y
app oaches, should bebene icial o u u e he apeu ic app oaches in
humans in i o.
To conclude, ex i o acu e and o gano ypic human cul u es p o ide
bene icial app oaches o unde s and human b ain de elopmen , aging,
e olu ion and diso de s. They could p o ide pa ien -o ien ed
he apeu ical medicine, in pa icula o d ug- esis an diso de s. Tha
is o say, he eme gence o such models equi es s anda ds adop ed by
he communi y, in e ms o expe imen al p o ocols ( issue
anspo a ion, cu ing inhibi o s, cul u e medium), quali y assessmen s
(elec ophysiology, mo phology, cul u e in ec ions), me ada a
managemen (age, sex, o igin, sociocul u al s a us, IQ, e c.) and e hical
s anda ds (communica ion, consen app o al & pos -mo em dona ions
in pa icula in child en and in ellec ual de iciency condi ions, genomic
expe imen s). Ano he key aspec is o imp o e he communica ion
be ween basic esea ch, clinicians, pa ien in ol emen and companies
o acili a e issue sha ing, explo a i e esea ch and d ug de elopmen .
Mo eo e , p eclinical d ug de elopmen , wha e e he p eclinical model
(ex i o, in i o, animal) equi es s ong ele ance o he ou come and
pa ame e s assessed ela ed o wha is expec ed in human indi iduals
(e.g., blood–b ain ba ie pene a ion, pha macokine ics and dynamics,
oxici y, dose selec ion, bioma ke s, end poin s), o ensu e highe
chance o ansla ion.
Discussion: singula i y, speci ici y, and
expe imen al app oaches
In his essay, Iha e explo ed mul iple laye s o di e gence in he
human lineage, om ea ly neu ode elopmen o neu onal p ope ies
and neu ocogni i e ea u es. None o hese di e ences a e s ic ly
“human-speci ic,” consis en wi h Da win’s iew ha mos di e ences
be ween humans and o he animals a e “o deg ee, no o kind”
(Riche son e al., 2021; Lindhou e al., 2024; Da win, 1871). The e o e,
Iad oca e o he concep o “species-singula i y” o “human species-
speci ici y” a he han claiming human uniqueness. The speci ici y o
human neu ode elopmen esul s om a complex in e play o
e olu iona y cellula mechanisms ha in luence b ain
cy oa chi ec u e, connec i i y, neu onal p ope ies, and ci cui
unc ion, culmina ing wi h enhanced cogni i e abili ies, in a cul u al
species (Pollen e al., 2023). The molecula mechanisms unde lying
hese p ocesses a e human-speci ic e olu iona y inno a ions
combined wi h hominid-, p ima e-, mammalian-, e eb a e-, and
me azoan-conse ed mechanisms (Lancas e , 2024; Tosches, 2021).
Human modi ie s modula e, e ine o combine ances al mechanisms
in an “e olu iona y inke ing” (Jacob, 1977).
Libé-Philippo 10.3389/ nsyn.2025.1672646
F on ie s in Synap ic Neu oscience 08 on ie sin.o g
In conclusion, while he meaning behind he s encils o human
hands emains beyond ou each, expe imen al biology enables us
o begin unde s anding he biological subs a es o human neu al
e olu ion and o species-speci ic sensi i i ies o
neu ode elopmen al and neu ological diso de s. Complemen a y
mul imodal and mul iscale app oaches a e bene icial o assess
speci ici ies o human neu al p ope ies, om he molecule o he
beha io al le els, which could lead in he u u e o he disco e y
o no el he apeu ic app oaches based on human-speci ic cellula
and molecula p ope ies.
Au ho con ibu ions
BL-P: W i ing– o iginal d a , W i ing– e iew & edi ing.
Funding
The au ho decla es ha inancial suppo was ecei ed o he
esea ch and/o publica ion o his a icle. BL-P esea ch eam is
suppo ed by he Eu opean Resea ch Council (ERC, “hCe ebE ol”
p ojec ), he A*MIDEX Founda ion (Ma seille, F ance), he F ench
CNRS agency and he F ench ATIP-A eni p og am.
Acknowledgmen s
I hank membe s o he IBDM and “Human neu onal e olu ion”
esea ch eam o scien i ic discussions, as well as he CBD and
Vande haeghen esea ch eam (CBD VIB– KU Leu en, Belgium) o
scien i ic con ibu ions and discussions. Figu es ha e been gene a ed
using Bio ende .
Con lic o in e es
BL-P is an in en o on a PCT applica ion ela ed o he wo k
on LRRC37B.
Gene a i e AI s a emen
The au ho decla es ha no Gen AI was used in he c ea ion o
his manusc ip .
Any al e na i e ex (al ex ) p o ided alongside igu es in his
a icle has been gene a ed by F on ie s wi h he suppo o a i icial
in elligence and easonable e o s ha e been made o ensu e accu acy,
including e iew by he au ho s whe e e possible. I youiden i y any
issues, please con ac us.
Publishe ’s no e
All claims exp essed in his a icle a e solely hose o he
au ho s and do no necessa ily ep esen hose o hei a ilia ed
o ganiza ions, o hose o he publishe , he edi o s and he
e iewe s. Any p oduc ha may bee alua ed in his a icle, o
claim ha may bemade by i s manu ac u e , is no gua an eed o
endo sed by he publishe .
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