Abstract

Some key features of Rett Syndrome (RTT), an autism spectrum disorder, are stereotypic hand movements, dystonia, and a dyspraxic gait. Since these symptoms all involve motor coordination, the abnormalities may stem from dysfunction in the cerebellum. Considering the role of dopamine in motor control, we hypothesize that dysfunction in dopaminergic signaling in the cerebellum is responsible for these motor deficits in RTT. Notably, there was limited data on dopaminergic pathway inputs to the cerebellum. Previous work in our lab shows clear dopamine expression in the cerebellum, and dopamine receptor type 1 (D1) distributed on Bergmann glial cells (BGCs) rather than Purkinje cells (PCs), the only neuronal output of the cerebellum. We aim to determine if dopaminergic fibers from the substantia nigra pars compacta (SNc) and locus coeruleus (LC) modulates PCs indirectly by regulating BGCs. We measured protein levels of glutamate AMPA receptor subunits and their phosphorylated versions by Western immunoblotting. Using immunohistochemistry (IHC) in brain sections from mice, we observed dopaminergic fibers originating in the SNc projecting to the cerebellum. By performing single-molecule fluorescence in situ hybridization (smFISH) in cerebellar sections, we located D1 receptors in BGCs, but not in PCs, implying that PCs are indirectly modulated. Future studies include implementing the deletion of D1 receptors selectively in BGCs to determine the consequences on motor function.