# Mechanisms of Central Synaptic Dysfunction in SMA

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $443,755

## Abstract

Project Summary
Motor circuits control fundamental behaviors such as swallowing, breathing and locomotion. Spinal motor
neurons are the key mediators translating motor commands generated within the central nervous system to
peripheral muscle targets. Motor neurons are activated by a precisely regulated pattern of synaptic activity
from sensory neurons, local spinal interneurons and descending pathways from the brain. During early
development, synaptic activity received by motor neurons shapes their functional properties. In contrast, gene
mutations that induce perturbations in either neuronal wiring or synaptic drive received by motor neurons often
result in motor system disorders. A prominent example of this situation is spinal muscular atrophy (SMA)—an
inherited neuromuscular disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein.
SMA pathogenesis involves alterations of multiple components of the motor circuit leading to abnormalities in
spinal reflexes, motor neuron loss and skeletal muscle atrophy. However, the molecular, cellular and circuit
mechanisms underlying SMA remain largely elusive. Our previous work have led us in uncovering novel
molecular perturbations involving the downregulation of the "delayed rectifier" potassium channel Kv2.1 as an
important determinant in the regulation of motor neuron firing. In addition, SMA motor neurons are under
increased tonic inhibitory originating from pre-motor inhibitory interneurons. Finally, we have identified
reduction of neurotrophin 3 (NT3) as a candidate for the selective vulnerability of motor circuits responsible for
activating proximal muscles which are more vulnerable compared to distal muscles. In Aim 1, we will study
whether increased inhibitory synaptic drive on motor neurons, acting non-cell autonomously, is responsible for
motor circuit dysfunction in SMA mice. We will employ mouse genetics together with morphological and
functional assays. In Aim 2, we will investigate whether the dynamic downregulation of the potassium "delayed
rectifier" channel Kv2.1 expression through abnormal dephopshorylation is a major contributor for the reduction
in MN repetitive firing in SMA. We will use ES-differentiated motor neurons co-cultured with interneurons that
have been engineered to downregulate SMN protein levels following antibiotic exposure. In addition, we will
use mouse models to determine the contribution of the main three enzymes reported to regulate Kv2.1
expression in neurons. In Aim 3, we will expand on our preliminary studies, which has identified reduction of
NT3 in SMA spinal cords early in the disease onset, to determine its relative contribution in the selective
vulnerability of motor circuits in SMA mice. Specific and selective upregulation of NT3 in motor neurons or
muscles will provide further insights into the source of NT3 impairment.

## Key facts

- **NIH application ID:** 9961677
- **Project number:** 5R01NS078375-09
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** George Z Mentis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $443,755
- **Award type:** 5
- **Project period:** 2012-04-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961677

## Citation

> US National Institutes of Health, RePORTER application 9961677, Mechanisms of Central Synaptic Dysfunction in SMA (5R01NS078375-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9961677. Licensed CC0.

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