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Glucagon‐like peptide‐1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis

Glucagon‐like peptide‐1 receptor differentially controls mossy cell activity across the dentate... Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. Less well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon‐like peptide‐1 (GLP‐1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal‐dependent mnemonic function, might regulate MC function through expression of its receptor, GLP‐1R. RNA‐seq demonstrated that most, though not all, Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1r‐ires‐Cre mice crossed with Ai14D reporter mice followed by co‐labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r‐expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP‐1R agonist exendin‐4 (5 μg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole‐cell patch‐clamp recordings from ventral MCs showed that bath application of exendin‐4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study adds to known MC activity modulators a neurohormonal mechanism that may preferentially affect ventral DG physiology and may potentially be targetable by several GLP‐1R pharmacotherapies already in clinical use. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Hippocampus Wiley

Glucagon‐like peptide‐1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis

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References (82)

Publisher
Wiley
Copyright
© 2022 Wiley Periodicals LLC.
ISSN
1050-9631
eISSN
1098-1063
DOI
10.1002/hipo.23469
Publisher site
See Article on Publisher Site

Abstract

Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. Less well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon‐like peptide‐1 (GLP‐1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal‐dependent mnemonic function, might regulate MC function through expression of its receptor, GLP‐1R. RNA‐seq demonstrated that most, though not all, Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1r‐ires‐Cre mice crossed with Ai14D reporter mice followed by co‐labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r‐expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP‐1R agonist exendin‐4 (5 μg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole‐cell patch‐clamp recordings from ventral MCs showed that bath application of exendin‐4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study adds to known MC activity modulators a neurohormonal mechanism that may preferentially affect ventral DG physiology and may potentially be targetable by several GLP‐1R pharmacotherapies already in clinical use.

Journal

Hippocampus – Wiley

Published: Nov 1, 2022

Keywords: dentate gyrus; GLP‐1; glucagon‐like peptide‐1 receptor; hippocampus; learning and memory; mossy cell

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