# Mechanism of dystroglycan function at inhibitory synapses.

> **NIH NIH F31** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $45,016

## Abstract

Project Summary
 Dystroglycan is a heavily glycosylated transmembrane receptor expressed in a wide variety of tissues
throughout development, including muscle and brain. Mutations in at least one of 18 genes reduce dystroglycan
glycosylation and function, causing a heterogeneous group of human congenital muscular dystrophies
(dystroglycanopathies) characterized by muscle weakness, cortical malformations, cognitive impairments, and
seizures. Within the brain, dystroglycan is highly expressed by glia and neurons. While dystroglycan has been
studied extensively for its role in regulating the integrity of the radial glial scaffold during cortical development,
the subsequent function of neuronal dystroglycan has remained elusive. Recently, a surprising requirement for
neuronal dystroglycan in the formation and maintenance of CCK/CB1R+ interneuron synapses was identified.
However, a detailed mechanistic understanding of how dystroglycan selectively regulates the formation and
maintenance of CCK/CB1R+ synapses is lacking. Based on these findings and my preliminary data, I will test
the hypothesis that dystroglycan expressed in excitatory neurons promotes survival and formation of
CCK/CB1R+ interneurons and their synapses in a glycosylation-dependent manner.
 This project will elucidate how dystroglycan functions at inhibitory synapses using a combination of
histological, slice electrophysiology, and imaging approaches in both in vivo genetic models and in vitro neuronal
cultures. Aim 1 will test the hypothesis that presynaptic CCK/CB1R+ interneurons undergo programmed cell
death in the absence of postsynaptic dystroglycan, and whether dystroglycan is required for the initial formation
or maintenance of functional synapses. Aim 2 will provide mechanistic insight into how dystroglycan promotes
inhibitory synaptogenesis by defining whether dystroglycan-mediated synapse formation requires its
glycosylation. These experiments will provide critical insight into the basic mechanisms by which neuronal
dystroglycan controls subtype-specific inhibitory synapse development. This study will also provide clues about
the molecular and cellular origins of specific neurological symptoms in dystroglycanopathy, ultimately helping to
inform development of therapeutic strategies for restoring dystroglycan glycosylation and brain function in
patients.

## Key facts

- **NIH application ID:** 9918160
- **Project number:** 5F31NS108522-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Daniel Scott Miller
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,016
- **Award type:** 5
- **Project period:** 2019-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918160

## Citation

> US National Institutes of Health, RePORTER application 9918160, Mechanism of dystroglycan function at inhibitory synapses. (5F31NS108522-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9918160. Licensed CC0.

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