Cerebellum circuits in neurodevelopmental disorders

Overview

Project Summary

The World Health Organization estimates that about 20% of people will experience a mental or behavioral disorder, underscoring the need to better understand their biological bases. Recent evidence highlights the cerebellum as a key contributor to neurodevelopmental disorders such as autism and intellectual disability, with findings including altered cerebellar–cortical connectivity, reduced cerebellar volume, and loss of Purkinje cells—changes linked to cognitive and social deficits. Beyond motor coordination, the cerebellum appears to support cognitive processes like associative learning and temporal prediction, though its higher-order roles remain unclear.

This project investigates cerebellar circuit dysfunction using a mouse model of intellectual disability carrying a CACNG2 (stargazin) missense mutation (V143L). Stargazin is crucial for AMPA receptor targeting and synaptic plasticity in the cerebellum. The mutant mice show abnormal neuronal features, impaired cognitive and social behavior, and deficits in cerebellum-dependent learning despite normal motor coordination and absence of ataxia—making them ideal for isolating learning-related cerebellar mechanisms.

Using morphological analyses, expansion microscopy, behavioral assays, and in vivo/ex vivo electrophysiology, the study aims to link specific cerebellar circuits and plasticity mechanisms to distinct cerebellum-dependent behaviors, identify disease-specific circuit deficits, and reveal potential therapeutic targets.

Project Details