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Research ArticleNegative Results, Disorders of the Nervous System

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

Simon Trent, Jeremy Hall, William M. Connelly and Adam C. Errington
eNeuro 17 June 2019, 6 (3) ENEURO.0364-18.2019; DOI: https://doi.org/10.1523/ENEURO.0364-18.2019
Simon Trent
1Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, United Kingdom
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Jeremy Hall
1Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, United Kingdom
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William M. Connelly
2School of Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia
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Adam C. Errington
1Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, United Kingdom
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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 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.

  • CYFIP1
  • dentate gyrus
  • GABA
  • neurodevelopmental
  • tonic inhibition

Footnotes

  • The authors declare no competing financial interests.

  • This work was supported by a Wellcome Trust Strategic Award (DEFINE). A.C.E. was supported by a Jane Hodge Foundation Neuroscience Fellowship, and S.T. is supported by a Neuroscience and Mental Health Research Institute Fellowship.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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eneuro: 6 (3)
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May/June 2019
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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
Simon Trent, Jeremy Hall, William M. Connelly, Adam C. Errington
eNeuro 17 June 2019, 6 (3) ENEURO.0364-18.2019; DOI: 10.1523/ENEURO.0364-18.2019

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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
Simon Trent, Jeremy Hall, William M. Connelly, Adam C. Errington
eNeuro 17 June 2019, 6 (3) ENEURO.0364-18.2019; DOI: 10.1523/ENEURO.0364-18.2019
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Keywords

  • CYFIP1
  • dentate gyrus
  • GABA
  • neurodevelopmental
  • tonic inhibition

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