DISTINCTIVE SYNAPTIC REMODELING PROPERTIES OF HIPPOCAMPAL NEURONS IN THE VALPROIC ACID RAT MODEL OF AUTISM

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

Mar del Plata

Congreso; LIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2019

Autism spectrum disorders (ASD) are characterized by impairments in social interaction and repetitive-stereotyped behaviors. These core symptoms imply alterations in brain areas of the limbic system including the hippocampus. Previously, we reported hippocampal alterations using the well- validated ASD animal model by prenatal exposure to valproic acid (VPA, 450 mg/kg ip). The hippocampus of juvenile VPA rats displayed decreased synaptic marker synaptophysin (SYN) along with an increased expression of the neural cell adhesion molecule (NCAM) and a decrease in its polysialylated form (PSA-NCAM). Also, neurons from VPA animals showed a smaller dendritic tree and fewer glutamatergic synapsis which also depicted the NCAM/PSA-NCAM imbalance in vitro. The aim of this study was to evaluate the remodeling properties of primary hippocampal neurons either from VPA or control male pups. After neuronal treatment (DIV13 or 7), cytoskeletal and synaptic markers were evaluated (DIV14) by immunocytochemistry. While in neurons from control animal glutamate (5 μM-3min, DIV13) induced an NMDA-dependent dendritic retraction and synaptophysin (SYN) puncta number reduction, neurons from VPA animals were only capable of dendritic retraction without any change in synapse number. When evaluating the response to fluoxetine (0.1 μM, DIV13), neurons from VPA animals were unable of remodeling their dendritic tree but SYN puncta number decreased. These changes were accompanied with increased PSA-NCAM expression only in VPA neurons. Similar effects were generated by a functional PSA mimetic peptide (DIV13) in the VPA group but not in the control one. A sialic acid precursor (DIV7) normalized synapse number and dendritic tree in neurons from VPA animals without affecting the control group. To sum up, our results indicate distinctive remodeling features of neurons from VPA animals and suggest that NCAM/PSA-NCAM balance modulation may play a key role in restoring synaptic and dendritic profile.