DISRUPTED CEREBELLAR FUNCTION AND SOCIAL DEFICITS IN A MOUSE MODEL OF SCHIZOPHRENIA WITH <EM>CACNG2</EM> MUTATION

The cerebellum, once primarily associated with motor coordination, is now recognized as a crucial contributor to the pathophysiology of neuropsychiatric disorders. Increasing evidence implicates cerebellar dysfunction in the social and cognitive deficits characteristic of Autism Spectrum Disorders and Schizophrenia, though the underlying mechanisms remain poorly understood.
In this study, we examined cerebellar alterations in a novel knock-in (KI) mouse line harboring a schizophrenia-linked mutation (STG-SN) in the CACNG2 gene, which encodes the synaptic protein stargazin. Stargazin is essential for synaptic delivery and regulation of AMPA receptors, processes fundamental to effective neurotransmission.
Behavioral analyses revealed sex-dependent abnormalities in social interaction and prepulse inhibition of the acoustic startle reflex – both phenotypes associated with schizophrenia. STG-SN KI mice also exhibited tendencies for increased behavioral despair, suggestive of a depressive-like phenotype. Despite intact motor coordination on the accelerating rotarod, these mice demonstrated impaired motor learning, a behavior reliant on cerebellar processing.
Considering that STG is abundantly expressed in Purkinje cells (PCs), the principal output neurons of the cerebellar cortex, we assessed their electrophysiological properties. Our recordings indicated an elevated intrinsic firing rate of PCs in STG-SN KI mice, consistent with cerebellar hyperexcitability. By contrast, the presence of synaptic inputs occludes these firing rate alterations in PCs, but leads to increased irregularity of action potential firing, suggesting cerebellar synaptic input deficits in these animals.
Collectively, these findings highlight a previously unappreciated role of stargazin in cerebellar function and strengthen the link between cerebellar circuit dysfunction and the emergence of social abnormalities relevant to neuropsychiatric disorders.