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Cyfip1 haploinsufficiency does not alter GABAA receptor δ-subunit expression and tonic inhibition in dentate gyrus PV+ interneurons and granule cells

Citation

Trent, S and Hall, J and Connelly, WM and Errington, AC, Cyfip1 haploinsufficiency does not alter GABAA receptor δ-subunit expression and tonic inhibition in dentate gyrus PV+ interneurons and granule cells, eNeuro, 6, (3) pp. ENEURO.0364-18.2019. ISSN 2373-2822 (2019) [Refereed Article]


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Copyright 2019 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1523/ENEURO.0364-18.2019

Abstract

Copy number variation (CNV) at chromosomal region 15q11.2 is linked to increased risk of neurodevelopmental disorders including autism and schizophrenia. A significant gene at this locus is cytoplasmic fragile X mental retardation protein (FMRP) interacting protein 1 (CYFIP1). CYFIP1 protein interacts with FMRP, whose monogenic absence causes fragile X syndrome (FXS). Fmrp knock-out has been shown to reduce tonic GABAergic inhibition by interacting with the δ-subunit of the GABAA receptor (GABAAR). Using in situ hybridization (ISH), qPCR, Western blotting techniques, and patch clamp electrophysiology in brain slices from a Cyfip1 haploinsufficient mouse, we examined δ-subunit mediated tonic inhibition in the dentate gyrus (DG). In wild-type (WT) mice, DG granule cells (DGGCs) responded to the δ-subunit-selective agonist THIP with significantly increased tonic currents. In heterozygous mice, no significant difference was observed in THIP-evoked currents in DGGCs. Phasic GABAergic inhibition in DGGC was also unaltered with no difference in properties of spontaneous IPSCs (sIPSCs). Additionally, we demonstrate that DG granule cell layer (GCL) parvalbumin-positive interneurons (PV+-INs) have functional δ-subunit-mediated tonic GABAergic currents which, unlike DGGC, are also modulated by the α1-selective drug zolpidem. Similar to DGGC, both IPSCs and THIP-evoked currents in PV+-INs were not different between Cyfip1 heterozygous and WT mice. Supporting our electrophysiological data, we found no significant change in hippocampal δ-subunit mRNA expression or protein level and no change in α14-subunit mRNA expression. Thus, Cyfip1 haploinsufficiency, mimicking human 15q11.2 microdeletion syndrome, does not alter hippocampal phasic or tonic GABAergic inhibition, substantially differing from the Fmrp knock-out mouse model.

Item Details

Item Type:Refereed Article
Keywords:CYFIP1, dental gyrus, GABA, neurodevelopment, tonic inhibition, autism, schizophrenia, fragile-x
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Central Nervous System
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Biological Sciences
UTAS Author:Connelly, WM (Dr William Connelly)
ID Code:134018
Year Published:2019
Deposited By:Medicine
Deposited On:2019-07-22
Last Modified:2019-08-30
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