Altered Inhibitory Synaptic Transmission and Changes in GABAergic Markers in the Hippocampus of Genetic and Environmental Animal Model of Autism.

Changes in hippocampal neurons are known to play a critical role in social memory deficits associated with autism spectrum disorders (ASD). Although the theory of excitatory-inhibitory imbalance in autism pathogenesis is well established, early developmental alterations in the hippocampus remain insufficiently characterized. Alterations in gamma-aminobutyric acid (GABA)ergic neurons and their markers are thought to underlie synaptic changes in inhibitory circuits. Therefore, this study was designed to: (1) quantify glutamatergic and GABAergic neuron populations in the hippocampus; (2) characterize inhibitory postsynaptic currents (IPSCs) in primary hippocampal neurons; and (3) assess gene expression of selected GABAergic markers in two autism-like animal models, namely Shank3-deficient mice and prenatally valproate (VPA)-exposed rats. A reduced proportion of GABAergic neurons was observed in the hippocampus of both models. An increase in the number of glutamatergic neurons was found only in the hippocampus of prenatally VPA-exposed rats. This was accompanied by a decrease in IPSC frequency in primary hippocampal neurons from prenatally VPA-exposed rats, while no significant changes were found in Shank3-deficient mice. Altered temporal dynamics of inhibitory synaptic transmission were demonstrated in both models by a decreased cumulative probability of inter-event intervals for inhibitory currents. Furthermore, reduced gene expression levels of Gabarap and Gabarapl1 were detected in Shank3-deficient mice, whereas decreased Gat1 expression level was found in prenatally VPA-exposed rats at postnatal day 5. These findings strongly support the excitatory-inhibitory imbalance hypothesis in ASD. Thus, genetic or environmentally induced GABAergic changes in the hippocampus may underlie hippocampus-dependent social memory alterations in ASD.