Altered synaptogenesis and synapse remodeling underlie hippocampal hypoconnectivity in an experimental model of autism

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

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2018

Autism spectrum disorders (ASD) are characterized by impairments in social interaction and repetitive-stereotyped behaviours. Although image studies have described local hyperconnectivity in the prefrontal cortex (PFC) of ASD patients, reports in the hippocampusare still not conclusive. This structure is implicated in exploration, learning and memory but also in emotion and social behaviour. Applyingthe well-validated ASD animal model by prenatal exposure to valproic acid (VPA 450mg/kg IP), we previously reported in the hippocampus of juvenile VPA rats:a decrease in the synaptic markersynaptophysin (SYN) along with an increasedexpressionof the neural cell adhesion molecule (NCAM) and a decrease initspolysialylated form (PSA-NCAM).The aim of this study was to evaluate synapse formation and remodeling of primary hippocampal neurons either from VPA or control male pups (postnatal days1-2),in the absence of glia. Cytoskeletaland synaptic markerswere evaluated (DIV7-14) by immunocytochemistryand Western Blot.At DIV 14, neurons from VPA animals displayed a reduced dendritic tree (reduced MAP2area),a reduced number of glutamatergic synapses (decreased vGLUT and PSD-95 puncta number and area) and NMDA receptor clusters (decreased NR1 puncta number and individual puncta area). These neurons also exhibited reduced number of functional synapses (FM4-64 labelling) which contained smaller vesicular pools; total NCAM expressionincreased while PSA-NCAM decreased.While in neurons from control animal glutamate(5µM-3min) induced an NMDA-dependent dendritic retraction and SYN puncta number reduction,neurons from VPA animals were only capable of dendritic retraction without any changeinsynapse number. Our results indicate that neurons from VPA animals form a lower number of glutamatergic synapses that exhibit a more adhesive and resistant profile to synaptic remodeling. Unlike to the hyperconnectivity proposed for the PFC, our findings suggest that neuronal alterations would contribute to hippocampal hypoconnectivity and reduced synaptic plasticity.