Jean-Pierre Bourgeois

JEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISjpbourg@pasteur.frHomo sapiens sapiensMacaca mulatta

sudditi ma cittadini ai quali vengono riconosciuti i diritti civili e politici (diritto dipartecipazione alle decisioni pubbliche, diritto di voto…). Per la prima volta si è di frontea documenti solenni (Bill of Right del 1689, la Costituzione degli Stati Uniti, laDichiarazione di diritti dell’uomo e del cittadino del 1789 in Francia) che ufficializzano idiritti inalienabili dei cittadini fondati sul principio in base al quale ogni persona è ugualedavanti alla legge.E’ necessario sottolineare però che il principio di uguaglianza giuridica, all’interno delloStato Liberale, anche se presente, viene solo toccato o comunque non rispettato nel modopiù coerente possibile. Occorrerà assistere ad un ulteriore passaggio storico affinché taleprincipio si concretizzi in uguaglianza non più solo formale ma anche sostanziale di frontealla legge: quello che porta alla nascita dello Stato Sociale (Welfare State). La datasimbolica, in questo caso, è il 1929. In seguito, infatti, alla crisi economica, gli Statiintrapresero la strada che portò alla nascita dei diritti sociali, economici e culturali (dirittoall’istruzione, all’assistenza medica..) anche se è solo con la proclamazione dellaDichiarazione Universale dei Diritti Umani avvenuta nel 1948 che le libertà fondamentalidell'individuo vennero sancite in maniera chiara e completa. Nonostante il carattere nonvincolante di questo atto, va ad esso riconosciuto il merito di aver contribuito alladiffusione, all'interno della comunità internazionale, della convinzione che l'individuo,8

Bourgeois JP Rakic P.Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage.J. Neuroscience. 1993; 13: 2801-2820.JEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISjpbourg@pasteur.fr

Page xxxiii in : Development of the Prefrontal Cortex. Krasnegor, Lyon, Goldman-Rakic Editors. Brookes publishing Co. 1997.JEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISjpbourg@pasteur.fr

Anderson S.A. Classey J.D. Condé F. Lund J.S. Lewis D.A. Synchronous development of pyramidal neuron dendriticspines and parvalbumin-immunoreactive chandelier neuron axon terminals in Layer III of macaque prefrontal cortex.Neuroscience. 1995; 67(1): 7-22.JEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISjpbourg@pasteur.fr

Bourgeois J.P. and Rakic P.Synaptogenesis in the occipital cortexof macaque monkey devoid of retinalinput from early embryonic stages.Eur. J. Neurosci. 1996; 8 : 942-950.JEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISjpbourg@pasteur.fr

Helmeke et.al., JUVENILE EMOTIONAL EXPERIENCE ALTERS SYNAPTIC INPUTS ON PYRAMIDALNEURONS IN THE ANTERIOR CINGULATE CORTEX. Cerebral Cortex. 2001; 11 : 717-727.CorticalLayerMaternal deprivation during the first 3 postnatal weeksresults in fewer shaft synapses on dendrites ofpyramidal neurons in layer II of cingulate cortexin the adult.JEAN-PIERRE BOURGEOIS. CNRS URA 2182. INSTITUT PASTEURPARIS jpbourg@pasteur.fr

Champagne DL et al. Maternal Care and hippocampal plasticity : Evidence for Experience-Dependent Structural plasticity, altered synaptic functionning, and differential responsivenessto Glucocorticoids and Stress. Journal of Neuroscience. june 4 2008; 28 (23) : 6037-6045.1.some young rats receive low levels of maternal licking/grooming during their firstpostnatal week,2.in CA1 hippocampal fields of these adult rats one observes :reduced expressions of Glucocorticoids and Mineralocorticoids receptorsreduced receptors NMDA receptor subunits NR2A & NR2BNO LTP in slices in vitro.deficits in spatial and non-spatial learning, spatial memory, etc ..reduced cholinergic innervationshorter dendriteslower densities of dendritic spinesJEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISjpbourg@pasteur.fr

Valor LM, et al. Network activity-independent coordinated gene expression programfor synapse assembly. Proc. Natl. Acad. Sci. 13 march 2007; 104 (11) : 4658-4663.Activity-independent expressionsof synaptic genes (no effect of TTX at any time):CAMkII,PSD 95,GluR1,NR2B,Synaptophysin,etc..JEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISjpbourg@pasteur.frActivity-dependent expressionsof synaptic genes (blocked by TTX, starting 8 DIV) :arc, c-fos,… (IEGs),BDNF,Cox 6a2,Kv 1.4, Kcna 4,Narp-Nptx2,etc..

1. NEONATAL SYNAPTOGENESIS IS A VERY ROBUST DEVELOPMENTAL EVENT2. NEONATAL ELABORATION OF SYNAPTOARCHITECTONY IS HIGHLY SENSITIVE TO THEENVIRONMENTDURING CRITICAL PERIODS, GENES AND ENVIRONMENT COOPERATECRITICAL PERIODSJEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISjpbourg@pasteur.fr

CRITICAL PERIODS OF SYNAPTOGENESIS AND INHIBITORY TONE IN MICE EXPERIMENTAL MODELSCOMPETING THALAMIC INPUTEXCITATORY SYNAPSESUPON POST-SYNAPTICCORTICAL NEURONSNicotinic switch:Liu Neff BergScience 2006; 314: 1610-1613.LEFT RIGHTEYE EYEEXCITATORYNICOTINIC SWITCH ?HIGHESTSYNAPTICCOMPETITIONINHIBITORYLOW TONEGABAERGIC RECEPTOR CHANNELSLOWSYNAPTICCOMPETITIONINHIBITORYHIGH TONEREINSTATEDSYNAPTICCOMPETITIONRESTORATIONOF SYNAPTICPLASTICITYIN ADULTCEREBRALCORTEXJEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISjpbourg@pasteur.frearing onseteyes openingP12/13visualacuity10-12°P28PEAKvisualacuity3-4°Morishita H & Hensch TK.Critical Period RevisitedCurr Op in Neurobiol2008; 18 : 101-107Valverde F.Synaptogenesis in primary visualcortex (V1) of the mouse.Brain Res. 1971; 33: 1-11.P19ONSETCRITICAL PERIODin V1 layers III/IVP39END

Morishita H., and Hensch TK. Critical Period Revisited.Current Opinion in Neurobiology. 2008; 18 : 101-107.EARLYPRE-CRITICAL PERIODDVLPTActivity-independentexpressions ofsynaptic genesCRITICAL PERIODActivity-dependent expressions of synaptic genesChondroitin sulphate proteoglycanscondense into Peri Neuronal NetsMATURECONSOLIDATEDSYNAPTICCIRCUITSEXCITATORY TONE(mostly glutamatergic)INHIBITORY TONE(mostly GABAergic)Myelin-derived factors such as Nogo,Myelin-Associated Glycoprotein, orOligodendrocyte-myelin glycoprotein,reduce axonal growthDe-acetylation of Histones reducesexpression of plasticity genesimmatureGABAergicinhibitoryinterneuronPVExtra-synapticimmatureGABA A-Receptors. ... .. .PVPost-synapticmatureGABA A-ReceptorsJEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISGlutamatergic excitatory pyramidal neuronjpbourg@pasteur.frPERI NEURAL NETPVHISTONEDEACETYLATIONAXONAL MYELINIZATION

Modified from :Bourgeois J.P.Acta Pædiatrica Suppl.1997; 422: 27-33.SYNAPTOGENESIS IN PRIMARY VISUAL AND PREFRONTAL CORTICESBIRTH3PUBERTYDEATHMOUSE AND RATBlue&Parnavelas, 1983deFelipe et al., 1997.NORMALIZED DENSITY OF SYNAPSESLGNLGNLGNBIRTH3V1V1V1BIRTH3PUBERTYBIRTH34PUBERTYDEATH4PUBERTYDEATHCATMACAQUEDEATHMANCragg, 1975Bourgeois,Goldman-Rakic,Rakic, 1993Huttenlocher &Dabholkar1997JEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISjpbourg@pasteur.fr10 10 2 10 3 10 4 10 5DAYS AFTER CONCEPTION (LOG SCALE)

Bourgeois, 1997.Acta Pœdiatrica Suppl.1997; 422 : 27-33.JEAN-PIERRE BOURGEOIS. CNRS URA 2182. INSTITUT PASTEUR. PARISjpbourg@pasteur.frEVOLUTION OF PHASE 3 OF SYNAPTOGENESISGESTATIONDURATION(in Days AfterConception=DAC)PUBERTYONSETPHASE 3DURATION(onset to end)DENSITYOFSYNAPSES(in millions permm 3 of corticaltissue)SYNAPSESPERNEURONTOTALNUMBEROFCORTICALAREASTOTALNUMBEROF« VISUAL »AREASRAT21 DAC82 DAC(2 months)14 DAYS(P2-P16)320-94612 500-13 500214-6CAT65 DAC248 DAC(6 months)30 DAYS(P9-P39)276-4065 800-9 30030-50 ?12-17MACAQUE165 DAC1260 DAC(3 years)136 DAYS(E90-P61)276-6202 000-5 6007225HUMAN280 DAC4660 DAC(12 years)470 DAYS(E120-P310)3506 800-10 000200 ?50 ?

2500 cm 2200 cm 2JEAN-PIERRE BOURGEOISCNRS URA 2182INSTITUT PASTEUR PARISjpbourg@pasteur.fr5 cm 2

Nous ne connaissons pas encore le code moléculaire spécifiant les réseaux synaptiques. Les ≈30 000gènes humains ne suffisent pas pour spécifier chacune des 10 14 -10 15 synapses formées dansle cortex cérébral humain. Pourtant, le physicien Michel Kerszberg a calculé que, je cite: "eachsynapse in the brain could be specified at the cost of roughly 50 molecular labels usedcombinatorially », in: Genes, Neurons and codes : remarks on biological communication. BioEssays. 2003; 25 :699-708. Selon son argument, il est même surprenant qu’il y ait de la plasticité synaptique dans lecortex cérébral. Mais la plasticité synaptique existe !Les molécules d’adhésion cellulaire (CAMs) présentes aux niveaux des membranes plasmiques préetpost-synaptiques pendant les synaptogenèses sont probablement impliquées dans ces mécanismesde spécifications synaptiques. D’une part, les faibles affinités de ces CAMs permettent de multiplesréorganisations dans les échafaudages moléculaires synaptiques. D’autre part, le très grand nombrede familles de CAMs observé dans le génome humain, ainsi que le grand nombre de sites d’épissagesalternatifs possibles, offrent une combinatoire très large, générant une immense diversité de cesprotéines.Je propose l’hypothèse suivante: cette combinatoire de CAMs permet les nombreux assemblagesdéassemblagesdes synapses nécessaires pour spécifier l’immense connectome du cortex cérébralhumain (JP Bourgeois. Acta Pædiatrica 1997; Suppl 422: 27-33; et le châpitre çi-joint). Les multiplesplasticités synaptiques qui se succèdent pendant l’histoire des individus, sont vraisemblablement lasource des mêmoires culturelles, des capacités créatrices de l’être humain, de ses abondantesfragilités mentales, mais aussi peut-être des futures thérapies synaptiques !