# Mechanisms of synaptic loss by the classical complement pathway in motor circuit development and disease

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $632,117

## 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 synaptic
dysfunction of proprioceptive origin as a key determinant event early in the disease process. Impaired function
and eventual loss of the sensory-motor excitatory synapses induce changes in the expression of channels on
the motor neuron membrane, resulting in reduced motor output. Unraveling therefore the molecular mechanisms
responsible for synaptic dysfunction and loss would provide key insights into the disease mechanisms. In Aim 1,
we will study whether complement proteins are responsible for the dysfunction and ultimately the elimination of
vulnerable synapses in in SMA mice. To address this, we will employ mouse genetics together with
morphological and functional assays. In Aim 2, we will investigate the role of certain key classical complement
proteins in the assembly and refinement of sensory-motor circuits during normal development. We will also use
mouse genetics, combined with morphological and functional assays to complete this part of the project. In Aim
3, we will probe into the molecular mechanisms that may cause the selective attack by aberrant activation of the
immune system towards synapses under ubiquitous SMN deficiency in mouse models of the disease.

## Key facts

- **NIH application ID:** 9971336
- **Project number:** 5R01AA027079-03
- **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:** $632,117
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971336

## Citation

> US National Institutes of Health, RePORTER application 9971336, Mechanisms of synaptic loss by the classical complement pathway in motor circuit development and disease (5R01AA027079-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971336. Licensed CC0.

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