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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

Trent, Simon ORCID:, Hall, Jeremy ORCID:, Connelly, William M and Errington, Adam C. ORCID: 2019. Cyfip1 haploinsufficiency does not alter GABAA receptor δ-subunit expression and tonic inhibition in dentate gyrus PV+ interneurons and granule cells. eNeuro 6 (3) , ENEURO.0364-18.2019. 10.1523/ENEURO.0364-18.2019

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Copy number variation 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. FMRP knock-out has been shown to reduce tonic GABAergic inhibition by interacting with the δ-subunit of the GABAA receptor. Using in situ hybridization, qPCR, western blot techniques and patch clamp electrophysiology in brain slices from a Cyfip1 haploinsufficient mouse, we examined δ-subunit mediated tonic inhibition in the dentate gyrus. In wild-type mice, dentate gyrus granule cells (DGGC) 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 DGGC. Phasic GABAergic inhibition in DGGC was also unaltered with no difference in properties of spontaneous inhibitory post synaptic currents (IPSCs). Additionally, we demonstrate that dentate gyrus granule cell layer PV+-interneurons (PV+-IN) 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+-IN were not different between Cyfip1 heterozygous and wild-type mice. Supporting our electrophysiological data, we found no significant change in hippocampal δ-subunit mRNA expression or protein level and no change in α1/α4 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. Significance StatementCYFIP1 is a candidate risk gene for neurodevelopmental and neuropsychiatric disorders. CYFIP1 protein interacts with FMRP whose loss downregulates tonic GABAergic inhibition via interaction with the δ-subunit of the GABAA receptor. Here, however, we report that reduced Cyfip1 dosage in mice does not alter tonic GABAergic inhibition in granule cells and PV+-interneurons of the dentate gyrus, a region rich in δ-subunit expression. Despite these negative findings, our data does demonstrate that PV+-interneurons of the DG granule cell layer are functionally regulated by tonic GABAergic inhibition, and in contrast to granule cells, this involves receptors incorporating both δ and α1-subunits. Thus, granule cell layer excitatory neurons and PV+-interneurons may be differentially modulated by subunit selective GABA receptor targeting drugs.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Society for Neuroscience: eNeuro
ISSN: 2373-2822
Funders: Wellcome Trust
Date of First Compliant Deposit: 20 June 2019
Date of Acceptance: 31 May 2019
Last Modified: 06 May 2023 10:10

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