# Effects of TrkB Activation on Abnormalities in Neocortical FS interneuron

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $38,310

## Abstract

Project Summary
Abnormalities in parvalbumin (PV) and somatostatin (SOM) interneurons are reported in a number of
neurological disorders, including epilepsy. Therapy that improves function of defective interneurons is not
available. Structural development and maintenance of interneurons is dependent on trophic support provided
by brain derived neurotrophic factor activation of TrkB receptors (TrkB-Rs). In the undercut (UC) model of
epileptogenic neocortical injury, chronic activation of TrkB-Rs with a selective small molecule partial agonist
(LM22A-4, “LM” below) has long-term effects to reverse structural and functional abnormalities in inhibitory
terminals of PV interneurons, enhance GABA release and increase the threshold for evoking epileptiform
activity and seizures. The parent grant main goal is to determine whether these effects will be applicable to
treatment or prevention of epilepsy in other models with different causes for seizures. The objective is to
determine whether chronic treatment with a TrkB-Rs partial agonist, by increasing GABA release from nerve
terminals of interneurons, or inducing new inhibitory synapse formation, will enhance inhibition in cortical
networks and suppress epileptiform discharges. The specific aims of the parent grant include to: i) test the
hypothesis that activation of TrkB-Rs with LM will reverse or prevent structural abnormalities in FS
interneurons of UC cortex; ii) Examine effects of TrkB-Rs activation on functional properties of GABAergic
inhibition in layer V; iii) Test the effects of LM on cortical network activity in UC animals. Proposed experiments
include a) immunocytochemistry and confocal imaging to assess alterations in presynaptic terminals of
interneurons; b) electrophysiological analysis of basic properties of inhibitory synaptic transmission from PV
interneurons to pyramidal neurons of in vitro slices to detect effects of TrkB activation on unitary IPSCs,
release probability and transmission failures. For this supplement grant we will study the effects of focal status
epilepticus (FSE) on numbers, morphology and physiology of GABAergic interneurons in the cortical network
and test possible mitigating effects of activation of TrkB-Rs with a small molecule partial agonist, PTXBD4-3
(BD). These results will complement and extend Aims 1, and 2 of the parent grant. Results of these
experiments will provide information about mechanisms leading from interneuronal abnormalities to
development of epilepsy and a potential approach to prophylaxis of epileptogenesis by enhancing trophic
support of interneurons. Considering the frequency and untoward consequences of FSE, results may have
potential translational importance.

## Key facts

- **NIH application ID:** 10304051
- **Project number:** 3R01NS082644-08S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** David Allan Prince
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,310
- **Award type:** 3
- **Project period:** 2021-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10304051

## Citation

> US National Institutes of Health, RePORTER application 10304051, Effects of TrkB Activation on Abnormalities in Neocortical FS interneuron (3R01NS082644-08S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10304051. Licensed CC0.

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