# Voltage-dependent ion channels controlling firing patterns of central neurons

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $536,783

## Abstract

The goal of the proposed research is to understand how the many types of ion channels present in a
single neuron work together to produce the firing patterns of that neuron. Ultimately, we hope to use this
knowledge to develop ion channel-targeted pharmacological agents that can differentially regulate firing
of different types of neurons and thereby treat pathophysiological behavior such as epilepsy and ataxias.
Previous grant periods focused on the functional roles of calcium channels, sodium channels, Kv2,
and Kv4 potassium channels. The focus in the next grant period is to understand how different potassium
channels combine to regulate the firing patterns of specific types of neurons and how inhibitors and
enhancers of particular potassium channels differentially modify firing patterns of different neurons. We
will follow up preliminary data showing that inhibition of BK and Kv3 potassium channels – including by
the clinically-used drug 4-aminopyridine - often causes paradoxical slowing rather than speeding of firing.
We will test two possible mechanisms for this effect: enhanced inactivation of Na channels or recruitment
of other potassium channels with slower deactivation. A key element is to compare action potential firing
in different types of neurons. We will focus on three examples of major electrophysiological phenotypes:
hippocampal CA1 pyramidal neurons, cerebellar Purkinje neurons, and midbrain dopamine neurons.
The experimental design will combine current clamp recordings of action potential firing with voltage-
clamp analysis of the underlying currents, using both intact neurons in brain slice and acutely dissociated
neurons, which allow fast voltage clamp to study gating on the rapid time scale of the action potential. A
key feature of the approach will be to study both action potential firing and channel gating kinetics at 37
°C. Current clamp and voltage clamp experiments will be directly linked by the action potential clamp
technique, in which recordings of natural firing behavior are used as voltage clamp commands to allow
pharmacological dissection of the components of current generating patterns of action potentials. The
research will include substantial characterization of pharmacological agents that block or enhance
potassium channel subtypes, both as experimental tools and as possible leads for clinical drugs.

## Key facts

- **NIH application ID:** 9838258
- **Project number:** 5R01NS036855-23
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** BRUCE P BEAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $536,783
- **Award type:** 5
- **Project period:** 1997-07-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838258

## Citation

> US National Institutes of Health, RePORTER application 9838258, Voltage-dependent ion channels controlling firing patterns of central neurons (5R01NS036855-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838258. Licensed CC0.

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