Etiology of cognitive deficits in neurodegenerative disease Spinocerebellar Ataxia Type 1

The cerebellum plays a role in prefrontal cortex (PFC) function and cognition. How chronic and progressive cerebellar dysfunction impacts PFC function and cognition remains less understood. Spinocerebellar ataxia type 1 (SCA1) is an inherited, fatal neurodegenerative disease caused by an abnormal expansion of glutamine (Q) encoding CAG repeats in the gene Ataxin-1 (ATXN1). Patients with SCA1 suffer from motor, cognitive and mood deficits, and severe loss of Purkinje cells (PCs) in the cerebellum.

We will discuss how PC dysfunction impacts PFC function and cognition in SCA1 using experiments in two different SCA1 mouse models.

We previously demonstrated impaired cognition in a transgenic SCA1 model, the ATXN1[82Q] line which expresses polyQ ATXN1 only in cerebellar Purkinje cells (PCs). To build on these results we will discuss our new findings on how cerebellar pathology can impacts the PFC of ATXN1[82Q] mice.

We will then present our findings using a novel conditional knock-in SCA1 model, f-ATXN1146Q mice at early disease stage, including increased number of neurons and increased density of excitatory synapses in the PFC.

Finally, we will discuss experiments aiming to precisely determine the contribution of cerebellar PCs in cognitive deficits in SCA1.

Our findings indicate that cerebellar dysfunction is sufficient to impact PFC, but when multiple brain regions are impacted in disease, cerebellar dysfunction may have a compensatory role in PFC dysfunction.

Learning Objectives: 

1. Summarize how disease pathogenesis differs in cerebellum and PFC.

2. Review how the dysfunction in cerebellum is sufficient to impact PFC at molecular and cellular levels.

3.  Describe how when both PFC and cerebellum are impacted, cerebellum may compensate for PFC dysfunction.