Homeostatic plasticity defects in autism: insight from human mutations in the CNTNAP2 gene

Overview

Project Summary

Emerging findings link Autism Spectrum Disorders (ASD) pathogenesis to a loss of homeostatic plasticity, a set of adaptive mechanisms that maintain neuronal network activity within dynamic boundaries. Recently, we and others have showed CNTNAP2-encoded protein CASPR2 as a novel regulator of glutamatergic synaptic transmission and experience-dependent homeostatic plasticity. We hypothesize that CASPR2 role in experience-dependent homeostatic plasticity is functionally hampered by ASD-associated CNTNAP2 mutations.
Herein, we will create a publicly available and curated database gathering genetic,
functional and clinical data from CNTNAP2 variants. Focusing on three ASD-related CNTNAP2 mutations, we will assess their in vitro damaging impact, notably the nanoscale synaptic composition disruption, perturbation of homeostatic plasticity adaptations and synchronous network activity in human neurons. Further, CASPRasd
variants impact on experience-dependent homeostatic plasticity will be evaluated in vivo.
This study will provide seminal insights on the synaptic, cellular and circuitry functions of CASPR2 hampered by ASD-associated CNTNAP2 mutations, and establish a causal link between disrupted homeostatic adaptations to sensory experience and ASD pathogenesis. Furthermore, this model may serve as a corollary to understand ASD pathogenesis and benefit the development of future experimental strategies.

Project Details