Impairment of GABAergic signaling and synaptic plasticity as key determinants for neurodevelopmental disorders: a study from NL3R451C knock-in mice, an animal model of autism

Autism Spectrum Disorders (ASDs) comprise a heterogeneous group of neuro-developmental disorders, often of genetic origin, characterized by impaired social interactions, communications deficits and stereotyped behavior. These disorders affect 1/150 children, particularly under the age of 3. In a few cases, ASDs have been found to be associated with single mutations in genes involved in synaptic function. One of these mutations (R451C), identified in a family with children affected by autism, involves a gene encoding for NLG3. This is a postsynaptic adhesion molecule that, interacting with its presynaptic partner neurexin, ensures the stabilization of synapses and the maintenance of an appropriate excitatory (E)/inhibitory (I) balance within specific brain areas. An altered E/I is present in several neuropsychiatric and neurodevelopmental disorders, including ASDs. Transgenic mice carrying the R451C mutation of NLG3 constitute an ideal animal model for studying ASDs In this proposal in vitro and in vivo electrophysiological techniques will allow studying whether, at early developmental stages, the NL3 mutation affects synaptic plasticity processes and gamma oscillations known to be involved in high cognitive functions. Synaptic plasticity is the process by which synapses are able to modify their strength in relation to the requests of the external word in experience and/or activity dependent manner. Learning is therefore an adaptive process that impacts on the dynamic properties of neuronal networks and on information processing. This study will shed light on cellular and molecular mechanisms underlying ASDs and will contribute to identify new molecular targets useful for developing therapeutic tools to cure these devastating disorders.