Haploinsufficiency Does Not Alter GABA Receptor δ-Subunit Expression and Tonic Inhibition in Dentate Gyrus PV Interneurons and Granule Cells.

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 protein interacts with FMRP, whose monogenic absence causes fragile X syndrome (FXS). knock-out has been shown to reduce tonic GABAergic inhibition by interacting with the δ-subunit of the GABA receptor (GABAR). Using hybridization (ISH), qPCR, Western blotting techniques, and patch clamp electrophysiology in brain slices from a 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 α-selective drug zolpidem. Similar to DGGC, both IPSCs and THIP-evoked currents in PV-INs were not different between 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 α/α-subunit mRNA expression. Thus, haploinsufficiency, mimicking human 15q11.2 microdeletion syndrome, does not alter hippocampal phasic or tonic GABAergic inhibition, substantially differing from the knock-out mouse model.