Hippocampal hypoconnectivity implies reduced number and size of glutamatergic synapses in the VPA rat model of autism

TRAETTA MARIANELA; CODAGNONE MARTIN; UCCELLI NONTHUE; MALLEVILLE CORPA MARÍA JOSÉ; ZÁRATE SANDRA; REINÉS ANALÍA

Congreso; II Reunión Conjunta de Sociedades de Biociencias; 2017

Autism spectrum disorders (ASD) are characterized by impairments in social interaction and repetitive-stereotyped behaviours. Strong genetic evidence regarding alterations in adhesion molecules and other synaptic proteins redefines ASD as developmental synaptophathies. A well validated ASD animal model, based on prenatal exposure to valproic acid (VPA), mimics the main behavioural and neuroanatomical alterations found in these disorders. We reported a decrease in synaptic protein synaptophysin (SYN) and the polysialylated form of neural cell adhesion molecule (PSA-NCAM)in the hippocampus of juvenile VPA rats. The aim of this study was to evaluate neuronal differentiation, synaptic formation and their temporal correlation with changes in hippocampal PSA-NCAM levels. PSA-NCAM expression was studied in the hippocampus of P3 male rat pups after in utero (E10.5) VPA (500 mg/kg) or saline exposure. SYN, PSA-NCAM, v-GLUTand PSD-95 expression profiles during differentiation and synaptic formationwere evaluated in hippocampal neuronal cultures (DIV7-14) either from P1-2 VPA or control male pups. Number of functional synapses and vesicular dynamic were measured by FM4-64 loading and unloading assays, respectively. PSA-NCAM expression decreasedin the VPA group before the in vivosynaptogenic peak. Once synaptogenesis reached its peak in vitro (DIV14), reducedSYN total puncta area accompanied with a profound decrease in v-GLUT and PSD95 puncta labelling was found. The PSA-NCAM expression diminution (DIV7) preceded the decrease in SYN puncta labelling seen in neurons from VPA animals (DIV10). FM4-64 experiments showed fewer functional synapses in the VPA group and although the vesicular pool proved to be smaller, unloading vesicle kinetic was conserved. Our results suggest that the early PSA-NCAM reduction seen in hippocampal neurons from VPA animalscould affect glutamatergic synapse formationand function by altering both synapse number and vesicular pool size.