The GLP-1 Receptor Agonist Exendin-4 and Diazepam Differentially Regulate GABAA Receptor-Mediated Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons.

Sergiy V Korol,Zhe Jin,Bryndis Birnir,Steven Barnes

doi:10.1371/journal.pone.0124765

Abstract

Glucagon-like peptide-1 (GLP-1) is a metabolic hormone that is secreted in a glucose-dependent manner and enhances insulin secretion. GLP-1 receptors are also found in the brain where their signalling affects neuronal activity. We have previously shown that the GLP-1 receptor agonists, GLP-1 and exendin-4 enhanced GABA-activated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. The hippocampus is the centre for memory and learning and is important for cognition. Here we examined if exendin-4 similarly enhanced the GABA-activated currents in the presence of the benzodiazepine diazepam. In whole-cell recordings in rat brain slices, diazepam (1 μM), an allosteric positive modulator of GABAA receptors, alone enhanced the spontaneous inhibitory postsynaptic current (sIPSC) amplitude and frequency by a factor of 1.3 and 1.6, respectively, and doubled the tonic GABAA current normally recorded in the CA3 pyramidal cells. Importantly, in the presence of exendin-4 (10 nM) plus diazepam (1 μM), only the tonic but not the sIPSC currents transiently increased as compared to currents recorded in the presence of diazepam alone. The results suggest that exendin-4 potentiates a subpopulation of extrasynaptic GABAA receptors in the CA3 pyramidal neurons.

Highlights

Over a number of years evidence has accumulated suggesting that diabetes mellitus increases the risk of impairment of cognitive functions [1,2,3,4,5]
In the present study we examined in rat hippocampal CA3 pyramidal neurons the effects of diazepam applied alone or together with exendin-4 on the GABAA receptor-mediated synaptic and tonic currents
We examined the effects of diazepam (1 μM) and exendin-4 (10 nM) on spontaneous inhibitory postsynaptic current (sIPSC) and tonic GABAA receptor-mediated currents recorded in the rat hippocampal CA3 pyramidal neurons

Summary

Introduction

Over a number of years evidence has accumulated suggesting that diabetes mellitus increases the risk of impairment of cognitive functions [1,2,3,4,5]. A number of mechanisms may be involved including decreased signaling by metabolic hormones. It is well established that the brain expresses receptors for many metabolic hormones, including receptors for insulin and the incretins, e.g. glucagon-like peptide-1 (GLP-1) [6]. It is, somewhat surprising that apart from the hypothalamus [7], we know relatively little about the effects of metabolic hormones on neurons and function of neuronal circuits and, thereby, brain function. Receptors for metabolic hormones are prominently expressed in the PLOS ONE | DOI:10.1371/journal.pone.0124765. Receptors for metabolic hormones are prominently expressed in the PLOS ONE | DOI:10.1371/journal.pone.0124765 April 30, 2015

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