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Pink Grain Wall

PROJECTS

  How do channel and receptor mutations lead to neurological disorders?

The Snell lab studies how dysfunction in channel and receptors lead to neurological disorders.  The cerebellum is responsible for coordination of motor movements, although recent evidence suggests that the cerebellum also contributes to non-motor tasks such as reward processing and social interaction, and that defects in cerebellar function lead to cognitive disorders including autism spectrum disorder (ASD). However, the underlying mechanism and contribution of the cerebellar circuitry to such tasks and disorders remains poorly understood. Cerebellar function relies on the regular pace-making firing of Purkinje cells, the main output neuron of the cerebellar cortex. The Snell lab is aimed at understanding 1) ion channel and neurotransmitter dynamics that set the intrinsic activity of cerebellar Purkinje cell and their synaptic output during normal motor and cognitive health, and 2) how dysfunction of these channels and receptors influences Purkinje cell function resulting in motor and cognitive disorders. We are investigating this at multiple levels, from channel function to cellular function, to network function and behavior in mouse models. Main Lab Questions: 1) Does the intrinsic pace-making of Purkinje cells and/or cerebellar synaptic transmission contribute to cognitive impairment? 2) Do the pathways underlying attacks in EA2 also underly symptoms in other episodic channelopathies and cerebellar motor disorders

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  How do mutations in the same channel lead to different neurological disorders and symptoms?

-We are interested in single nucleotide polymorphisms (SNPs) which result in a change in a single-nucleotide of a genome, and how mutations in the same gene can result in different neurological disorders. -We Investigate this through the lens of calcium channel mutations, specifically the pore forming subunit of the Cav2.1 channel. Mutations in this channel result in Episodic Ataxia, Familial Hemiplegic migraine, and more recently a subset of patients have been identified with intellectual disabilities.

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  What is the effect of Cav2.1 channel mutations on channel properties?

- Attacking this question from multiple levels and with multiple model systems will allow us to make discoveries that will help us elucidate the underlying mechanism and lead to possible therapeutic interventions for patients. - We collaborate with the Kurshan lab at Albert Einstein college of medicine, experts in utilizing the c-elegans model for investigation of channel and synaptic function.

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  What is the effect of Cav2.1 channel mutations on cellular and network function?

- The Cav2.1 channel is expressed throughout the CNS, with particularly high expression postsynpatically on cerebellar Purkinje cells. - We will leverage our expertise in motor impairment that results from calcium channel mutations to investigate if these mechanisms underly the non-motor impairments caused by Cav2.1 channel mutations.

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   Are the mechanisms underlying stress and caffeine induced attacks shared among other trigger induced episodic disorders?

- Stress and caffeine underlying episodic symptoms in several channelopathies, such as Episodic Ataxia type 1 (EA1) and paroxysmal non-kinesigenic dyskinesia (PNKD), with the mechanism underlying episodes remaining unknown. - It is also well established that modulation of Purkinje cell activity underlies many cerebellar motor disorders, such as SCA’s, with the exact pathway remaining unknown. The Snell lab will investigate the contribution of Purkinje cell pace-making and the mechanisms of trigger-induced and baseline motor impairment in episodic channelopathies and cerebellar motor disorders.

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A new direction for the Snell lab

- We will utilize and build off of the work already conducted by the Hatten lab to differentiate human induced pluripotent stem cells (IPSCs) into cerebellar Purkinje cells from patients with Cav2.1 channel mutations, to further investigate the effect of the mutations on Purkinje cell function and channel expression. - Samples will be provided by the CACNA1A foundation and work will be conducted in conjunction with the Yale IPSC NeuroCore, led by Dr. Joao Pereira.

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