# Mechanisms and Functions of Synapses and Circuits

> **NIH NIH R35** · HARVARD MEDICAL SCHOOL · 2021 · $924,845

## Abstract

Project Summary
The ultimate goal of this grant is to determine how synapses and circuits function in vivo to control behaviors.
One major focus is to clarify the mechanisms of short-term plasticity, and to understand the functional and
behavioral role of short term plasticity at different synapses. Although synaptic plasticity plays a crucial role
throughout the brain, and dysfunction has been implicated in numerous neurological disorders, the many
interacting forms of plasticity remain poorly understood. We will focus on the hypothesis that specialized
calcium sensors respond to presynaptic calcium signals to enhance neurotransmitter release. Our findings
suggest that facilitation and posttetanic potentiation (PTP) use 2 different types of calcium sensors to enhance
transmission on different time scales. Facilitation is a form of synaptic enhancement that lasts for hundreds of
milliseconds. We have found that facilitation is mediated by synaptotagmin 7 (syt7), which is a calcium-
sensitive isoform with slow kinetics. In preliminary studies we find that in syt7 knockout mice, facilitation is
eliminated even though the initial probability of release and presynaptic calcium signals are unaltered. Viral
expression of syt7 restores facilitation in syt7 knockout animals. These studies indicate that we have identified
the long sought after calcium sensor for facilitation. Future studies will clarify the role of syt7 in facilitation in
contributing to different behaviors. PTP is a form of synaptic enhancement lasting for tens of seconds following
a period of high-frequency firing of presynaptic neurons. We have recently shown that PKCβ is a calcium
sensor for PTP at the calyx of Held. We will continue to clarify the mechanism of PTP and ultimately plan to
use molecular genetics to selectively eliminate PTP from specific synapses to determine the role of PTP in
different behaviors.
A second major focus is to clarify cerebellar circuitry and understand how different circuit elements contribute
to cerebellar function, which regulates motor learning, sensorimotor integration and social behaviors. We have
recently shown that all Purkinje cells (PCs) have collaterals that target many types of cells within the cerebellar
cortex, even in adults. This indicates it is necessary to consider feedback from the output of PCs to the
cerebellar cortex. We will determine if PCPC synapses promote synchronous activity also test the
hypothesis that synaptically-connected PCs converge onto the same DCN neuron and regulate its firing.
These studies will extend our understanding of cerebellar processing and will provide important insights into
neurological disorders that arise from cerebellar dysfunction. We will also determine how specific regions of the
cerebellar cortex regulate specific behaviors.

## Key facts

- **NIH application ID:** 10066370
- **Project number:** 5R35NS097284-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** WADE G REGEHR
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $924,845
- **Award type:** 5
- **Project period:** 2016-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066370

## Citation

> US National Institutes of Health, RePORTER application 10066370, Mechanisms and Functions of Synapses and Circuits (5R35NS097284-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10066370. Licensed CC0.

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