# Activity-Dependent Regulation of Kv4 Channels

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2021 · $357,731

## Abstract

Kv4 channels have been shown to play important roles in modulating neural activity: regulating the
integration of high-frequency trains of synaptic input, regulating backpropagating action potentials, and
contributing to long-term potentiation. Consequently, mutations that affect Kv4 function/availability have been
shown to result in spatial learning defects, seizure behavior, as well as temporal lobe epilepsy. In the last
funding period, we showed that expression and turnover of Kv4 channels are affected in three new contexts: in
modulating cholinergic synaptic homeostasis, in response to over-expression of human Aβ42, and during
normal aging. In the proposed studies, we investigate the mechanisms underlying Kv4 expression during
cholinergic synaptic homeostasis. Synaptic homeostasis/scaling is a form of plasticity that has been heavily
studied in the last decade as a protective mechanism that counterbalances changes in global neural activity;
this likely occurs during physiological processes, such as learning/memory and development, as well as during
pathological conditions. We used Drosophila central neurons as a model, and showed that Drosophila α7
(Dα7) nAChRs are up-regulated after cholinergic blockade, thereby enhancing synaptic currents and providing
a homeostatic response. We found that this homeostatic response triggered a novel regulatory mechanism –
the up-regulation of Kv4 channels, which we showed prevents an “overshoot” of the homeostatic response.
We further showed that the up-regulation of Kv4 channels is blocked by transcriptional inhibitors, and is
dependent on Dα7 nAChRs and Ca2+ influx. Drosophila continues to be an ideal model system for these
studies because of its cholinergic CNS, the genetic tools it offers, its less redundant genome (eg. there is only
a single Drosophila NFAT and Kv4 gene, each of which represents a multi-gene family in mammals), and the
ability to go from mechanisms of gene regulation to physiological relevance in the intact brain, and eventually,
whole animal behavior. The proposed studies will apply new optogenetic approaches to elicit cholinergic
synaptic homeostasis in vivo (Aim-1) –something that has not been explored in any system, and which would
currently not be feasible in mammalian systems. We will examine underlying molecular mechanisms, including
a novel relationship between α7 nAChRs and Kv4 channels (Aim-2), and inactivity-induced transcription of Kv4
(Aim-3) that is mediated by NFAT (Aim-4). We will also test all molecular mechanisms for their physiological
relevance in identified neurons in the intact brain. Our studies are likely to reveal important insights into the
underlying mechanisms of cholinergic synaptic homeostasis.

## Key facts

- **NIH application ID:** 10176513
- **Project number:** 5R01GM083335-13
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** SUSAN L TSUNODA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,731
- **Award type:** 5
- **Project period:** 2007-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176513

## Citation

> US National Institutes of Health, RePORTER application 10176513, Activity-Dependent Regulation of Kv4 Channels (5R01GM083335-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10176513. Licensed CC0.

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