# Inhibitory synapses and axon regeneration in adults after injury-induced axotomy

> **NIH NIH R21** · EMORY UNIVERSITY · 2020 · $195,000

## Abstract

Motor and sensory nerves regenerate in the periphery after being axotomized following nerve injuries. This
capacity allows some functional recovery, however this is frequently suboptimal being the relative inefficiency
of axon regeneration a major problem, particularly for injuries at some distance from muscle. Axotomy induces
genetic changes in motoneurons that promote axon growth, yet this is rather slow taking months or years for
axons to reach their targets after limb injuries. This compounds with the fact that the regenerative capacity of
motoneurons is limited to a short temporal window and that chronic denervation results in muscle atrophy, as
well as changes in central circuits, all impairing recovery. Therefore there is renewed interest on mechanisms
to promote axon regeneration. One mechanism recently highlighted and intensely studied by one of the P.I.s
(Dr. A.W. English) is the effect of activity and exercise in promoting axon regeneration. However, this approach
is limited since patients are frequently either with the affected limbs immobilized or in bed rest preventing
implementation of adequate exercise programs. We now seek proof for a mechanistic explanation that could
be recruited also with passive rehabilitation and/or pharmacology. After axotomy motoneurons increase their
excitability and shed excitatory synapses while maintaining inhibitory synapses. In addition, the potassium
chloride co-transporter isoform 2 (KCC2) is downregulated changing the nature of inhibitory synapses from
hyperpolarizing to depolarizing. The other P.I. in this proposal (Dr. F.J. Alvarez) is an expert in spinal inhibitory
interneurons and synapses. Together, both P.I.s hypothesized that after axotomy inhibitory synapses are the
main drivers of motoneuron activity and could stimulate axon regeneration. There is a strong scientific premise
for this hypothesis: GABA actions promote axon elongation during early development and manipulations that
enhanced preservation of inhibitory synapses on axotomized motoneurons correlated with faster functional
recovery. To directly test whether inhibitory synaptic activity on axotomized motoneurons promotes axon
regeneration we propose in Aim 1 to block inhibitory synapses on axotomized motoneurons using tetanus
neurotoxin A and study the effects on motor axon regeneration and muscle reinnervation. In Aim 2 we will use
mouse models to genetically define the interneurons targeting the cell body of regenerating motoneurons and
that could provide a depolarizing synaptic drive. We will then use genetically-encoded activity modifiers to
examine whether their activity influences motor axon regeneration. Resolution of these aims will reveal for the
first time whether inhibitory synapse activity is a driving force for axon regeneration in the adult and the spinal
neurons that might be responsible. This is of high significance from a translational point of view since it will
point to new approaches to enhance “inhibitory” dri...

## Key facts

- **NIH application ID:** 10020198
- **Project number:** 5R21NS114839-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** FRANCISCO J ALVAREZ
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,000
- **Award type:** 5
- **Project period:** 2019-09-30 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020198

## Citation

> US National Institutes of Health, RePORTER application 10020198, Inhibitory synapses and axon regeneration in adults after injury-induced axotomy (5R21NS114839-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10020198. Licensed CC0.

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