Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Cerebellar pathology in the absence of plasticity gating


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PROJECT SUMMARY/ABSTRACT Dystrophin deficiency, which occurs in Duchenne muscular dystrophy (DMD), results in muscle wasting. As dystrophin is expressed in the brain, its deficiency also contributes to neurological symptoms in DMD patients. Cerebellar Purkinje cells in mouse models of DMD have weaker inhibitory synaptic connections and compromised climbing-fiber-evoked plasticity. This implicates cerebellar dysfunction as a contributing factor to the neurological pathophysiology of DMD. Yet, how cerebellar dysfunction ultimately explains DMD neurological symptoms remains incompletely understood. Increasing evidence points to the importance of plasticity gating to maintain a reserve capacity for learning. In Purkinje cells, a candidate gating mechanism of plasticity induction is inhibition from molecular layer interneurons, which suppresses the evoked calcium response to climbing fiber excitation that triggers induction of long-term depression (LTD). Therefore, the objective of this study is to test for a potential synergistic role of inhibitory synapse weakening and compromised LTD in dystrophinopathy and determine if increasing GABAA receptor responsiveness specifically in Purkinje cells restores a high threshold for plasticity induction and thus provide a potential therapeutic strategy to ameliorate cerebellar dysfunction. We will employ a multidisciplinary approach encompassing the use of ex vivo and in vivo functional recordings in Purkinje-cell-autonomous dystrophin-deficient mice, cell-type specific neuropharmacological perturbations, and behavioral analyses. Through two aims, we will test correlative and causative links between aberrant neural circuit responsiveness, spurious plasticity, and cerebellar learning abnormalities. Completion of these aims will contribute novel insights into plasticity regulation, the etiology of neurological impairment in DMD, and potential avenues for treating cerebellum-related symptoms of this disorder.
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R01NS123933

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Collapse start date
2021-07-01
Collapse end date
2026-04-30

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