# Effects of TrkB Activation on Abnormalities in Neocortical FS interneuron

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $76,473

## Abstract

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 (BDNF) activation of TrkB receptors. 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. In order to determine whether these effects will be applicable to treatment or prevention
of epilepsy in other models with different causes for seizures, such as genetic epilepsies, the Dravet syndrome
(DS) mouse will be used in some experiments. Decreases in a membrane sodium channel in PV interneurons
in DS mice causes decreased release of the inhibitory transmitter GABA, and development of spontaneous
and high temperature-induced seizures. A variety of experimental approaches in DS and UC mice will be used
to determine whether chronic treatment with LM, by increasing GABA release from nerve terminals of SOM
and PV interneurons, or inducing new inhibitory synapse formation, will enhance inhibition in cortical networks
and suppress epileptiform discharges: 1) immunocytochemistry and confocal imaging will be used to assess
alterations in PV and SOM presynaptic terminals, including changes in expression of VGAT- and GAD65/67-
IR, and the calcium sensor protein synaptotagmin 2; 2) analysis of density of SOM/- and PV/gephyrin close
appositions to test for new inhibitory synapse formation induced by TrkB activation; 3) 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;
3) laser scanning photostimulation of cortical slices from PV/CHR2 and SOM/CHR2 mice to map the
distribution and strength of inhibitory connectivity in neocortical inhibitory circuits; and 4) video/EEG monitoring
of implanted mice to assess effects of treatment with LM on spontaneous seizures and hyperthermia-induced
seizures. 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.

## Key facts

- **NIH application ID:** 10598731
- **Project number:** 3R01NS082644-10S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** David Allan Prince
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $76,473
- **Award type:** 3
- **Project period:** 2013-04-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598731

## Citation

> US National Institutes of Health, RePORTER application 10598731, Effects of TrkB Activation on Abnormalities in Neocortical FS interneuron (3R01NS082644-10S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10598731. Licensed CC0.

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