# Cerebellar pathology in the absence of plasticity gating

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $482,542

## Abstract

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.

## Key facts

- **NIH application ID:** 10289334
- **Project number:** 1R01NS123933-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Jason M Christie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $482,542
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10289334

## Citation

> US National Institutes of Health, RePORTER application 10289334, Cerebellar pathology in the absence of plasticity gating (1R01NS123933-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10289334. Licensed CC0.

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