# Molecular Mechanisms Regulating Inhibitory Circuitry in the Spinal Cord

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $364,543

## Abstract

Establishing specific neuronal circuits is fundamental for the generation of coordinated muscle function.
However, the signals underlying the specificity of connection between interneurons and their targets in the
mammalian central nervous system (CNS) remain largely unknown to date. Our long-term research goal is to
understand the rules of interneuron circuit wiring and the molecular mechanisms that control it. The objective of
the proposed research is to describe how a combination of adhesive and neurotrophic signals determine
GABAergic interneuron circuit connectivity. A class of GABAergic interneurons, termed GABApre, forms synaptic
contacts with the terminals of proprioceptive sensory afferents, and thus directly controls proprioceptive sensory
input through an inhibitory strategy known as presynaptic inhibition. We will test the hypothesis that the
connectivity of a class of spinal GABAergic neurons varies between functionally-distinct sensory neurons and
that this connectivity is mediated via (ii) differential expression of muscle-derived neurotrophin (NT)-3 and (ii) a
matrix of IgSF adhesion proteins. The rationale underlying this proposal is that through understanding the
mechanisms underlying GABAergic interneuron circuit formation, we will enhance our understanding of — and
ultimately control over — inhibitory neuronal circuit development and function in vivo. We will test our hypothesis
with the following three aims: #1) Determine the functional specificity of GABAergic interneuron circuitry; #2)
Investigate the influence of muscle-derived NT-3 on GABApre synapse formation; and #3) Assess the role of
Contactin-5 in GABApre-sensory synapse formation. In the first aim, we combine timed tamoxifen injections,
mouse genetics and CTb labeling to analyze whether the specific connectivity of individual GABApre
interneurons may be functionally relevant. In the second aim, we examine the expression of Gabrg1 in
functionally distinct proprioceptive sensory neurons and assess consequences of changing NT-3 levels on both
Gabrg1 expression and GABApre terminal number. In the third aim, we perturb cell adhesion signaling using
mouse genetics and perform phenotypic analysis using molecular, micro-anatomic and functional assays,
including an electrophysiological measure of presynaptic inhibition. We also use an in vitro binding assay to
screen for new adhesion molecule candidates relevant for GABApre synaptic specificity in vivo. The research
proposed in this application is innovative because it combines a molecularly-defined interneuronal circuit with a
unique constellation of methodologies to integrate functional specificity with target-derived signals. The research
will provide an understanding of functional diverse GABApre circuitry and also advance our understanding of
how basic circuit paradigms may be adapted for diverse motor functions. The proposed work is significant
because it will contribute to fundamental knowledge of the formation of cir...

## Key facts

- **NIH application ID:** 9929656
- **Project number:** 5R01NS083998-07
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Julia Anna Kaltschmidt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,543
- **Award type:** 5
- **Project period:** 2013-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929656

## Citation

> US National Institutes of Health, RePORTER application 9929656, Molecular Mechanisms Regulating Inhibitory Circuitry in the Spinal Cord (5R01NS083998-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9929656. Licensed CC0.

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