Synapse formation and remodeling unveil aglutamatergic/GABAergic imbalance in hippocampal neurons in the VPA model of autism.

UCCELLI NA; CODAGNONE M; REINÉS A; TRAETTA M; ZÁRATE S

Congreso; ISN-ASN Meeting; 2019

ISN-ASN

Autism spectrum disorders (ASD) are characterized by impairmentsin social interaction and repetitive-stereotyped behaviors.Although increased cortical excitatory-inhibitory (E-I) ratio has beendescribed in ASD patients, results in the hippocampus are notconclusive. Using the valproic acid (VPA) model of ASD, wereported in the hippocampus of VPA rats a reduction in the synapticmarker synaptophysin along with an increased adhesive/nonadhesiveform expression ratio of the neural cell adhesion molecule(NCAM). This study aimed to evaluate E-I balance, synapseformation and remodeling in primary hippocampal neurons eitherfrom VPA or control male pups. Synaptic markers were evaluatedby immunocytochemistry and western blot. At DIV14, hippocampalneurons from VPA animals displayed a reduced dendritic tree(reduced MAP-2 area), a reduced number of glutamatergic synapses(decreased vGLUT puncta number and area) and NMDA receptorclusters (decreased NR1 puncta number and individual puncta area)but no changes in gabaergic synapses (conserved GAD-67 punctanumber). These neurons also exhibited reduced number of functionalsynapses (FM4-64 labelling) which contained smaller vesicularpools with preserved unloading kinetics; total NCAMexpression increased while its non-adhesive form (PSA-NCAM)decreased. While in neurons from control animals glutamateexposure (5 μM-3 min) induced an NMDA-dependent dendriticretraction and synapse number reduction, neurons from VPAanimals only exhibited dendritic retraction. Our results indicate thatneurons from VPA animals form fewer glutamatergic synapses witha more adhesive and resistant profile to synaptic remodeling,suggesting an underlying mechanism that would contribute toreduced structural synaptic plasticity in the hippocampus.