NL-4 IN AUTISM · Investigating the role of Neuroligin-4 in the development of autism-related synaptic and behavioral abnormalities in mice

Autism is a frequent neurodevelopmental disorder, characterized by impairments in social interaction, language deficits, and repetitive behaviors. The biological basis of autism remains unknown, and no cure or effective pharmacological treatment is currently available. Given the high prevalence of autism and the devastating consequences for patients and families, it is essential to improve our understanding of the molecular mechanisms underlying autism and to identify potential therapeutic approaches.According to an important new concept that has arisen over recent years, autism may be a ‘synaptopathy’, i.e. a disorder resulting from an aberrant development and function of synaptic connections in the brain. In support of this hypothesis, autism-related mutations have recently been identified in a number of proteins that play an essential role at synapses. In particular, several different mutations in the synaptic adhesion molecule Neuroligin-4 (NL-4) have been linked to autism, making this one of the most frequent monogenic causes of non-syndromic autism known to date. However, little is known about the molecular mechanisms by which NL-4 affects synapse development, or how loss of function of NL-4 may lead to the cognitive and behavioral impairments characteristic of autism.Here, we propose to address this issue by investigating the effects of constitutive and inducible manipulations of the NL-4 gene in mice, using a combination of molecular, physiological, and behavioral techniques. This approach will allow for a detailed characterization of the role of NL-4 in synapse formation and maintenance. This, in turn, will enable us to elucidate the relationship between NL-4-induced synaptic abnormalities and autism-related behaviors. Our study will greatly contribute to the understanding of the role of synaptic proteins in the pathogenesis of autism, and will generate important animal models for the development and validation of potential therapeutic strategies.