# The Action Potential as a Modulator of Synaptic Transmission

> **NIH NIH F31** · DARTMOUTH COLLEGE · 2020 · $45,520

## Abstract

Project Summary
 The action potential (AP) is a command signal that sharply controls the activity of voltage-gated Ca2+
channels (Cavs) and neurotransmission. The AP waveform has traditionally been considered to be a uniform,
binary signal as it propagates across an axonal arbor, however recent work has suggested there is a surprising
amount of variability in the width of the waveform arising from a heterogeneous distribution of voltage-gated Na+
and K+ channels across synapses. In the hippocampus, neurons burst in high frequency trains that undergo
waveform broadening though it is unclear what the ramifications of this broadening are. A fundamental gap exists
in understanding how variations in the AP waveform mechanistically affect neurotransmission as an experimental
approach is required with subcellular resolution that can integrate at the microsecond time scale. The
development of optogenetics has provided opportunities for manipulating and imaging activity within the small
en passant synapses of the central nervous system such as in the hippocampus. These experiments will provide
the first optical measurements of presynaptic APs, Ca2+ influx and exocytosis in single hippocampal neurons.
Modulation of the AP waveform is achieved pharmacologically by inhibiting a family of voltage-gated K+ channels
which results in a predictable broadening of the AP. An unexpected phenotype occurs with this treatment in
excitatory neurons: a dramatic increase in exocytosis corresponds with a minimal increase in Ca2+, suggesting
an uncoupling of the clearly defined Ca2+ and vesicle fusion relationship and an enhancement of synaptic
efficacy. The central hypotheses of this proposal are that a broadened AP waveform alters the Ca2+ contribution
of a specific Cav isoform, changes the radius of Ca2+ microdomains and/or differentially activates vesicle fusion
machinery. The overall objective of this proposal is to investigate the mechanisms behind the transduction of an
electrical action potential signal to the chemical release of neurotransmitter. The long-term goals are to
determine how heterogeneity of the AP waveform informs synaptic strength and plasticity.
Specific Aim 1 will determine how waveform broadening modulates presynaptic Cav isoform contribution using
selective toxins to isolate specific isoforms with and without a broadened AP. Specific Aim 2 will determine how
AP shape alters Ca2+ microdomains and vesicle exocytosis. Using optogenetics, gene silencing and
pharmacology these experiments will demonstrate if AP broadening influences the radius of microdomains or
differentially activates the protein Ca2+ sensors that mediate exocytosis. Given the complexity of this system as
well as the essential nature of electrical signaling in excitable cells it is unsurprising that mutations in the voltage-
gated channels which control the shape of the AP are implicated in several diseases including epilepsy, ataxia
and arrhythmias. Due to the role the AP plays as a...

## Key facts

- **NIH application ID:** 10025383
- **Project number:** 5F31NS110192-02
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Lauren C Panzera
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-09-12 → 2021-09-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10025383

## Citation

> US National Institutes of Health, RePORTER application 10025383, The Action Potential as a Modulator of Synaptic Transmission (5F31NS110192-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10025383. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*