Direction of action of presynaptic GABAA receptors is highly dependent on the level of receptor activation

Shailesh N. Khatri, Wan Chen Wu, Ying Yang, Jason R Pugh

Research output: Contribution to journalArticle

Abstract

Many synapses, including parallel fiber synapses in the cerebellum, express presynaptic GABAA receptors. However, reports of the functional consequences of presynaptic GABAA receptor activation are variable across synapses, from inhibition to enhancement of transmitter release. We find that presynaptic GABAA receptor function is bidirectional at parallel fiber synapses depending on GABA concentration and modulation of GABAA receptors in mice. Activation of GABAA receptors by low GABA concentrations enhances glutamate release, whereas activation of receptors by higher GABA concentrations inhibits release. Furthermore, blocking GABAB receptors reduces GABAA receptor currents and shifts presynaptic responses toward greater enhancement of release across a wide range of GABA concentrations. Conversely, enhancing GABAA receptor currents with ethanol or neurosteroids shifts responses toward greater inhibition of release. The ability of presynaptic GABAA receptors to enhance or inhibit transmitter release at the same synapse depending on activity level provides a new mechanism for fine control of synaptic transmission by GABA and may explain conflicting reports of presynaptic GABAA receptor function across synapses. NEW & NOTEWORTHY GABAA receptors are widely expressed at presynaptic terminals in the central nervous system. However, previous reports have produced conflicting results on the function of these receptors at different synapses. We show that presynaptic GABAA receptor function is strongly dependent on the level of receptor activation. Low levels of receptor activation enhance transmitter release, whereas higher levels of activation inhibit release at the same synapses. This provides a novel mechanism by which presynaptic GABAA receptors fine-tune synaptic transmission.

Original languageEnglish (US)
Pages (from-to)1896-1905
Number of pages10
JournalJournal of neurophysiology
Volume121
Issue number5
DOIs
StatePublished - May 1 2019

Fingerprint

Presynaptic Receptors
GABA-A Receptors
Synapses
gamma-Aminobutyric Acid
Synaptic Transmission
Direction compound
GABA Receptors
Presynaptic Terminals
Cerebellum
Neurotransmitter Agents
Glutamic Acid

Keywords

  • cerebellum
  • GABA
  • parallel fiber
  • presynaptic

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

Cite this

Direction of action of presynaptic GABAA receptors is highly dependent on the level of receptor activation. / Khatri, Shailesh N.; Wu, Wan Chen; Yang, Ying; Pugh, Jason R.

In: Journal of neurophysiology, Vol. 121, No. 5, 01.05.2019, p. 1896-1905.

Research output: Contribution to journalArticle

@article{b8ca36e679e14fa6b29463a7025f8c23,
title = "Direction of action of presynaptic GABAA receptors is highly dependent on the level of receptor activation",
abstract = "Many synapses, including parallel fiber synapses in the cerebellum, express presynaptic GABAA receptors. However, reports of the functional consequences of presynaptic GABAA receptor activation are variable across synapses, from inhibition to enhancement of transmitter release. We find that presynaptic GABAA receptor function is bidirectional at parallel fiber synapses depending on GABA concentration and modulation of GABAA receptors in mice. Activation of GABAA receptors by low GABA concentrations enhances glutamate release, whereas activation of receptors by higher GABA concentrations inhibits release. Furthermore, blocking GABAB receptors reduces GABAA receptor currents and shifts presynaptic responses toward greater enhancement of release across a wide range of GABA concentrations. Conversely, enhancing GABAA receptor currents with ethanol or neurosteroids shifts responses toward greater inhibition of release. The ability of presynaptic GABAA receptors to enhance or inhibit transmitter release at the same synapse depending on activity level provides a new mechanism for fine control of synaptic transmission by GABA and may explain conflicting reports of presynaptic GABAA receptor function across synapses. NEW & NOTEWORTHY GABAA receptors are widely expressed at presynaptic terminals in the central nervous system. However, previous reports have produced conflicting results on the function of these receptors at different synapses. We show that presynaptic GABAA receptor function is strongly dependent on the level of receptor activation. Low levels of receptor activation enhance transmitter release, whereas higher levels of activation inhibit release at the same synapses. This provides a novel mechanism by which presynaptic GABAA receptors fine-tune synaptic transmission.",
keywords = "cerebellum, GABA, parallel fiber, presynaptic",
author = "Khatri, {Shailesh N.} and Wu, {Wan Chen} and Ying Yang and Pugh, {Jason R}",
year = "2019",
month = "5",
day = "1",
doi = "10.1152/jn.00779.2018",
language = "English (US)",
volume = "121",
pages = "1896--1905",
journal = "Journal of Neurophysiology",
issn = "0022-3077",
publisher = "American Physiological Society",
number = "5",

}

TY - JOUR

T1 - Direction of action of presynaptic GABAA receptors is highly dependent on the level of receptor activation

AU - Khatri, Shailesh N.

AU - Wu, Wan Chen

AU - Yang, Ying

AU - Pugh, Jason R

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Many synapses, including parallel fiber synapses in the cerebellum, express presynaptic GABAA receptors. However, reports of the functional consequences of presynaptic GABAA receptor activation are variable across synapses, from inhibition to enhancement of transmitter release. We find that presynaptic GABAA receptor function is bidirectional at parallel fiber synapses depending on GABA concentration and modulation of GABAA receptors in mice. Activation of GABAA receptors by low GABA concentrations enhances glutamate release, whereas activation of receptors by higher GABA concentrations inhibits release. Furthermore, blocking GABAB receptors reduces GABAA receptor currents and shifts presynaptic responses toward greater enhancement of release across a wide range of GABA concentrations. Conversely, enhancing GABAA receptor currents with ethanol or neurosteroids shifts responses toward greater inhibition of release. The ability of presynaptic GABAA receptors to enhance or inhibit transmitter release at the same synapse depending on activity level provides a new mechanism for fine control of synaptic transmission by GABA and may explain conflicting reports of presynaptic GABAA receptor function across synapses. NEW & NOTEWORTHY GABAA receptors are widely expressed at presynaptic terminals in the central nervous system. However, previous reports have produced conflicting results on the function of these receptors at different synapses. We show that presynaptic GABAA receptor function is strongly dependent on the level of receptor activation. Low levels of receptor activation enhance transmitter release, whereas higher levels of activation inhibit release at the same synapses. This provides a novel mechanism by which presynaptic GABAA receptors fine-tune synaptic transmission.

AB - Many synapses, including parallel fiber synapses in the cerebellum, express presynaptic GABAA receptors. However, reports of the functional consequences of presynaptic GABAA receptor activation are variable across synapses, from inhibition to enhancement of transmitter release. We find that presynaptic GABAA receptor function is bidirectional at parallel fiber synapses depending on GABA concentration and modulation of GABAA receptors in mice. Activation of GABAA receptors by low GABA concentrations enhances glutamate release, whereas activation of receptors by higher GABA concentrations inhibits release. Furthermore, blocking GABAB receptors reduces GABAA receptor currents and shifts presynaptic responses toward greater enhancement of release across a wide range of GABA concentrations. Conversely, enhancing GABAA receptor currents with ethanol or neurosteroids shifts responses toward greater inhibition of release. The ability of presynaptic GABAA receptors to enhance or inhibit transmitter release at the same synapse depending on activity level provides a new mechanism for fine control of synaptic transmission by GABA and may explain conflicting reports of presynaptic GABAA receptor function across synapses. NEW & NOTEWORTHY GABAA receptors are widely expressed at presynaptic terminals in the central nervous system. However, previous reports have produced conflicting results on the function of these receptors at different synapses. We show that presynaptic GABAA receptor function is strongly dependent on the level of receptor activation. Low levels of receptor activation enhance transmitter release, whereas higher levels of activation inhibit release at the same synapses. This provides a novel mechanism by which presynaptic GABAA receptors fine-tune synaptic transmission.

KW - cerebellum

KW - GABA

KW - parallel fiber

KW - presynaptic

UR - http://www.scopus.com/inward/record.url?scp=85066918544&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066918544&partnerID=8YFLogxK

U2 - 10.1152/jn.00779.2018

DO - 10.1152/jn.00779.2018

M3 - Article

C2 - 30892973

AN - SCOPUS:85066918544

VL - 121

SP - 1896

EP - 1905

JO - Journal of Neurophysiology

JF - Journal of Neurophysiology

SN - 0022-3077

IS - 5

ER -