CogniStar: Cognitive Disorders as Defects in Synaptic Function : Insight from utations in the CACNG2 Gene

Overview

Project Summary

Intellectual disability (ID) and schizophrenia are cognitive disorders involving disruption of neuronal circuits, but treatments fail to target specific neuroplasticity deficits. Recent genetic studies show overlap of risk genes for these disorders, in particular of genes encoding synaptic proteins. However, it remains unknown how synaptic dysfunction resulting from pathogenic mutations impacts neuronal function and behavior. In subsets of ID and schizophrenia patients with different mutations in the CACNG2 gene encoding the synaptic protein stargazin, alterations in both shared and distinct neuronal mechanisms result in disease phenotypes. We are generating knock-in mice expressing stargazin human variants, and will determine whether these mice have differential behavioral, circuits, morphological and synaptic phenotypes, and explore a new therapeutic strategy. These studies will identify common and differential behavioral and functional phenotypes associated to ID and schizophrenia.

Main Goals

We focus on two missense human mutations in the CACNG2 gene, one identified in a non-syndromic ID patient, the other recently found by us in a family with schizophrenic patients. Our in vitro analyses showed that these mutations affect the neuronal surface mobility of stargazin, glutamate receptor traffic and synaptic plasticity. We generated knock-in mice expressing the stargazin ID or schizophrenia human variants. With these mice we are determining whether they have differential behavioral, circuits, morphological and synaptic phenotypes. Finally, we are exploring a new therapeutic strategy, found to modulate the function of stargazin, as a potential treatment to alleviate the complex symptoms of cognitive disorders. These studies will allow us to gain insight into mechanisms underlying stargazin-associated diseases, will lead to the identification of behavioral and functional phenotypes differentially associated to ID and schizophrenia, and will pave the way for novel therapeutic strategies.

Project Details