Synapses are dynamically regulated on the time scale of milliseconds to minutes by the interaction of many forms of plasticity. Such dynamic regulation is poorly understood, even though it plays many crucial roles within the brain and has been implicated in numerous neurological disorders. Our primary goals are to determine the mechanisms and functional consequences of short-term plasticity. By studying multiple forms of plasticity at different types of synapses we will be able to discern general features and synapse-specific specializations tailored to specific functional roles. (1) We will begin by studying posttetanic potentiation (PTP), a widely observed form of use-dependent synaptic enhancement lasting for tens of seconds following high-frequency activation. It had long been thought that sustained presynaptic calcium (Ca) increases contribute to PTP, but the molecular basis of PTP is unclear. We have recently shown that at the calyx of Held PTP is mediated by Ca-dependent protein kinase C. We will now test the hypothesis that PKC senses Ca and produces PTP by phosphorylating Munc18-1, and determine how presynaptic Ca and PKC activation control the time course of PTP. (2) We will also study synaptic regulation that arises from modulation of presynaptic Ca channels. A hallmark of synaptic transmission is that small changes in Ca influx produce large changes in release. This has been thought to arise entirely from alterations in the probability of release and reflect the Ca dependence of synaptotagmin. Remarkably, we find that changes in the effective pool size make large contributions to the Ca dependence of release. We will test the hypothesis that neuromodulators that reduce Ca influx also regulate release in part by decreasing the effective vesicle pool size. (3) Synaptic enhancement can arise by either activating presynaptic ionotropic receptors or subthreshold somatic depolarization. These forms of plasticity involve small depolarizations of presynaptic boutons, but their molecular mechanisms are not known. We will test the hypothesis that they are mediated by a common mechanism: depolarization elevates presynaptic Ca, which activates PKC to enhance release. (4) We will also use optogenetics to overcome current limitations in the study of short-term plasticity. Virtually nothing is known about many important synapses because they cannot be selectively activated with extracellular stimulation in brain slice. Optogenetic tools allow these synapses to be activated, but desensitization and slow kinetics could limit this approach. We will critically evaluate the ability of optogenetic tools to repetitiely activate axons reliably. When appropriate conditions are found, optogenetics will be used to study aspects of short-term plasticity that can't be studied with conventional approaches. Together, these studies will provide new insights into short-term plasticity, and will contribute t the application of new approaches to studying short-term plasticity.

Public Health Relevance

These studies will provide insight into the mechanisms and functional consequences of short-term synaptic plasticity, which dynamically regulate the strength of every synapse in the brain. They will lead to a deeper understanding of how synapses perform computations, and these studies are directly relevant to numerous neurological disorders that involve proteins implicated in short-term plasticity, such as Parkinson's disease, epilepsy and schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032405-20
Application #
8662809
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Talley, Edmund M
Project Start
1995-05-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
20
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Biology
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Jackman, Skyler L; Chen, Christopher H; Chettih, Selmaan N et al. (2018) Silk Fibroin Films Facilitate Single-Step Targeted Expression of Optogenetic Proteins. Cell Rep 22:3351-3361
Turecek, Josef; Regehr, Wade G (2018) Synaptotagmin 7 Mediates Both Facilitation and Asynchronous Release at Granule Cell Synapses. J Neurosci 38:3240-3251
Jackman, Skyler L; Regehr, Wade G (2017) The Mechanisms and Functions of Synaptic Facilitation. Neuron 94:447-464
Turecek, Josef; Jackman, Skyler L; Regehr, Wade G (2017) Synaptotagmin 7 confers frequency invariance onto specialized depressing synapses. Nature 551:503-506
Kaeser, Pascal S; Regehr, Wade G (2017) The readily releasable pool of synaptic vesicles. Curr Opin Neurobiol 43:63-70
Guo, Chong; Witter, Laurens; Rudolph, Stephanie et al. (2016) Purkinje Cells Directly Inhibit Granule Cells in Specialized Regions of the Cerebellar Cortex. Neuron 91:1330-1341
Thanawala, Monica S; Regehr, Wade G (2016) Determining synaptic parameters using high-frequency activation. J Neurosci Methods 264:136-152
Witter, Laurens; Rudolph, Stephanie; Pressler, R Todd et al. (2016) Purkinje Cell Collaterals Enable Output Signals from the Cerebellar Cortex to Feed Back to Purkinje Cells and Interneurons. Neuron 91:312-9
Jackman, Skyler L; Turecek, Josef; Belinsky, Justine E et al. (2016) The calcium sensor synaptotagmin 7 is required for synaptic facilitation. Nature 529:88-91
Tang, Jonathan Cy; Drokhlyansky, Eugene; Etemad, Behzad et al. (2016) Detection and manipulation of live antigen-expressing cells using conditionally stable nanobodies. Elife 5:

Showing the most recent 10 out of 71 publications