Skip to main content

Research Repository

Advanced Search

Cyfip1 Haploinsufficiency Does Not Alter GABAA Receptor d-Subunit Expression and Tonic Inhibition in Dentate Gyrus PV+ Interneurons and Granule Cells

Trent, Simon; Hall, Jeremy; Connelly, William M.; Errington, Adam C.

Cyfip1 Haploinsufficiency Does Not Alter GABAA Receptor d-Subunit Expression and Tonic Inhibition in Dentate Gyrus PV+ Interneurons and Granule Cells Thumbnail


Authors

Jeremy Hall

William M. Connelly

Adam C. Errington



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 d-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 d-subunit mediated tonic inhibition in the dentate gyrus (DG). In wild-type (WT) mice, DG granule cells (DGGCs) responded to the d-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 d-subunit-mediated tonic GABAergic currents which, unlike DGGC, are also modulated by the a1-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 d-subunit mRNA expression or protein level and no change in a1/a4-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.

Journal Article Type Article
Acceptance Date May 31, 2019
Publication Date Jun 17, 2019
Publicly Available Date Mar 28, 2024
Journal eneuro
Print ISSN 2373-2822
Publisher Society for Neuroscience
Peer Reviewed Peer Reviewed
Volume 6
Issue 3
Pages ENEURO.0364 - 18.2019
DOI https://doi.org/10.1523/ENEURO.0364-18.2019
Keywords CYFIP1, dentate gyrus, GABA, neurodevelopmental, tonic inhibition.
Publisher URL https://www.eneuro.org/content/6/3/ENEURO.0364-18.2019

Files




You might also like



Downloadable Citations