Mechanisms underlying altered GABAergic signaling in the hippocampus of transgenic mice carrying the human R451C mutation of the NLG3 gene: an animal model of autism

Autistic syndromes comprise a group of heterogeneous neuro-developmental disorders, mainly of genetic origin, characterized by impaired social interactions, communications deficits and stereotyped behaviors (either with mental retardation or with enhanced cognitive abilities), which affect 1/150 children particularly under the age of 3. In a few cases, ASD have been found to be associated with a single mutation in genes involved in synaptic function. These include a mutation in the gene encoding for NLG3 a postsynaptic adhesion molecule which together with its binding partner Nrnx bridges the synaptic cleft and ensures a corrected cross-talk between post and presynaptic specializations and the maintenance of the E/I balance. Transgenic mice carrying the human NLG3 R451C mutation constitute an ideal animal model for studying ASDs since these animals exhibit impaired social interactions and enhanced spatial learning abilities reminiscent of those present in some ASD patients. In addition, these mice display an increased GABA-A-mediated synaptic transmission in the forebrain. In this study, a multidisciplinary approach (including electrophysiology, imaging, immunocytochemistry, molecular biology and behavior), will be used to verify the hypothesis that early developmental changes in GABAergic signaling in NLG3 R451C KI mice affects the dynamic properties of neuronal networks and information processing in the hippocampus. Experiments performed at single cell level will allow assessing possible deficits in network activity, in the E/I balance, in the lateral diffusion of GABA-A receptors. Molecular biology tools will be used to identify the mechanisms determining synapse specificity of NLG3. This study will contribute to better understand the mechanisms of ASD in humans leading to the identification of molecular targets useful for developing new therapeutic tools for the cure of these devastating disorders.