UCSF

Ever since Hodgkin and Huxley described the sodium dependence in action potential nearly 70 years ago, neuroscientists have discovered an entire family of voltage-gated sodium channels (NaVs) in neuronal cells. Uncovering the differential distributions of these NaV isoforms between and within each type of neuron helped us understand the distinct roles they play in cellular functions. So crucial to normal neuronal physiology, genetic variants that result in protein structure changes can cause pronounced alteration in brain function and lead to disease. NaV1.2, encoded by SCN2A, is one NaV isoform whose genetic variants have been linked to neurodevelopmental disorders such as autism spectrum disorder (ASD). Studies have uncovered the importance of NaV1.2 in neuronal intrinsic properties and synaptic physiology in the forebrain. However, how these channels maintain normal cellular functions in the cerebellum, in which some of the strongest expression of NaV1.2 are detected, is unclear. The cerebellum is heavily implicated in ASD due to its functions in motor learning, fine movement control, and more recently discovered, cognition. Therefore, understanding how SCN2A dysfunctions alter cerebellar circuit has become critical to study disease manifestation in channelopathies. In my thesis work, I found that Scn2a haploinsufficiency in mice decreased cerebellar granule cell excitability, impaired high-frequency action potential propagation along their axons, and ultimately compromised the downstream synaptic plasticity that is critical to cerebellar learning. I also used cerebellum-dependent vestibulo-ocular reflex (VOR) to uncover that mice with Scn2a heterozygosity exhibited saturated VOR gain and deficit in VOR adaptation, which are correlated with abnormal Purkinje cell firing pattern during behavior. In addition, children with LoF SCN2A variants showed a similarly elevated baseline VOR gain. Lastly, I revealed that the VOR adaptation deficit in mice can be rescued by upregulating Scn2a in the entire mouse brain using a novel CRISPR activation technique. I hope this work will contribute to our understanding of sodium channel function in the cerebellum and ASD.