Cerebellar granule cell dysfunction in Shank3 mutant mice

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PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) is a complex neurological disorder associated with a broad collection of genetic mutations and environmental factors. While identifying the neural underpinnings of ASD has been a major focus in the field of genetics and neuroscience, it is not clear which brain region (s) and cell types may be functioning abnormally to give rise to ASD. The cerebellum, a brain region typically considered to be involved in motor coordination and control, has received considerable attention for its potential role in ASD, with a growing body of clinical evidence correlating ASD diagnoses with abnormalities in cerebellar anatomy, function, and motor or vestibular behaviors/functions. In parallel, cerebellar involvement in circuits outside of the motor system provides a substrate for the cerebellum to influence non-motor behaviors and processes, setting the stage for the importance of appropriate cerebellar function in a host of neural processes. Within the cerebellum, the initial integration of all incoming sensorimotor information entering the cerebellar cortex is carried out by the morphologically simple and extremely dense population of granule cells. These granule cells also express many high risk ASD-linked genes, especially those involved in synaptic transmission and development. However, little is known about the role and importance of many ASD-linked genes in the cerebellum, especially in granule cells. It is also not clear what aspects of cerebellar granule cell function and connectivity may be important for shaping certain non-motor (and motor) behaviors. To address this knowledge gap, in aims 1 and 2 we propose to identify the degree to which an ASD-linked gene determines properties of cerebellar granule cell synaptic interactions and cortical circuitry dynamics over time. In Aim 3, we will identify how a particular ASD-linked gene in cerebellar granule cells influence behavioral phenotype across motor and non-motor domains. Results from the proposed work will be key in identifying a mechanistic link between a gene/protein linked to ASD and specific synaptic abnormalities in the cerebellum.