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

TRAETTA ME; CODAGNONE MG; UCCELLI NA; MALLEVILLE CORPA MJ; REINÉS A; ZÁRATE S

Mar del Plata

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

Sociedad Argentina de Investigación Clínica (SAIC)

Autism spectrum disorders (ASD) are characterized by impairmentsin social interaction and repetitive-stereotyped behaviours. Althoughimage 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. Applying the well-validated ASD animal model by prenatal exposureto valproic acid (VPA 450mg/kg IP), we previously reported in thehippocampus of juvenile VPA rats: a decrease in the synaptic marker synaptophysin (SYN) along with an increased expression of theneural cell adhesion molecule (NCAM) and a decrease in its polysialylated form (PSA-NCAM). The aim of this study was to evaluatesynapse formation and remodeling of primary hippocampal neuronseither from VPA or control male pups (postnatal days 1-2), in theabsence of glia. Cytoskeletal and synaptic markers were evaluated (DIV7-14) by immunocytochemistry and Western Blot. At DIV14, neurons from VPA animals displayed a reduced dendritic tree(reduced MAP2 area), a reduced number of glutamatergic synapses (decreased vGLUT and PSD-95 puncta number and area) andNMDA receptor clusters (decreased NR1 puncta number and individual puncta area). These neurons also exhibited reduced numberof functional synapses (FM4-64 labelling) which contained smallervesicular pools; total NCAM expression increased while PSA-NCAMdecreased. While in neurons from control animal glutamate (5µM3min) induced an NMDA-dependent dendritic retraction and SYNpuncta number reduction, neurons from VPA animals were only capable of dendritic retraction without any change in synapse number.Our results indicate that neurons from VPA animals form a lowernumber of glutamatergic synapses that exhibit a more adhesiveand resistant profile to synaptic remodeling. Unlike to the hyperconnectivity proposed for the PFC, our findings suggest that neuronalalterations would contribute to hippocampal hypoconnectivity andreduced synaptic plasticity.