Ectopic Expression of α6 and δ GABA_AReceptor Subunits in Hilar Somatostatin Neurons Increases Tonic Inhibition and Alters Network Activity in the Dentate Gyrus

Abstract

The role of GABA A receptor (GABA A R)-mediated tonic inhibition in interneurons remains unclear and may vary among subgroups. Somatostatin (SOM) interneurons in the hilus of the dentate gyrus show negligible expression of nonsynaptic GABA A R subunits and very low tonic inhibition. To determine the effects of ectopic expression of tonic GABA A R subtypes in these neurons, Cre-dependent viral vectors were used to express GFP-tagged GABA A R subunits (␣6 and ␦) selectively in hilar SOM neurons in SOM-Cre mice. In singletransfected animals, immunohistochemistry demonstrated strong expression of either the ␣6 or ␦ subunit; in cotransfected animals, both subunits were consistently expressed in the same neurons. Electrophysiology revealed a robust increase of tonic current, with progressively larger increases following transfection of ␦, ␣6, and ␣6/␦ subunits, respectively, indicating formation of functional receptors in all conditions and likely coassembly of the subunits in the same receptor following cotransfection. An in vitro model of repetitive bursting was used to determine the effects of increased tonic inhibition in hilar SOM interneurons on circuit activity in the dentate gyrus. Upon cotransfection, the frequency of GABA A R-mediated bursting in granule cells was reduced, consistent with a reduction in synchronous firing among hilar SOM interneurons. Moreover, in vivo studies of Fos expression demonstrated reduced activation of ␣6/␦-cotransfected neurons following acute seizure induction by pentylenetetrazole. The findings demonstrate that increasing tonic inhibition in hilar SOM interneurons can alter dentate gyrus circuit activity during strong stimulation and suggest that tonic inhibition of interneurons could play a role in regulating excessive synchrony within the network.

Determination of the Effects of Sevoflurane Anesthesia in Different Maturing Stages of the Mouse Hippocampus by Transcriptome Analysis

“…The GABAA receptors increase tonic inhibition in somatostatin interneunons and alter circuit activity within the dentate gyrus [26]. GABAA receptors are also known to be a potential target of volatile anesthetics [27].…”

The enigmatic mossy cell of the dentate gyrus

“…Mossy cells express lower levels of STEP than HIPP cells (based on immunohisto-chemistry 128 ), but even a low expression level of STEP could contribute to their vulnerability given its importance for the vulnerability of HIPP cells 128 . HIPP and other hilar cells, including mossy cells, also have low levels of the δ-subunit of type A GABA receptors, which normally contributes to GABAergic inhibition, and therefore low levels of this subunit could make a cell vulnerable to excitotoxicity 129 .…”

New boundaries and dissociation of the mouse hippocampus along the dorsal‐ventral axis based on glutamatergic, GABAergic and catecholaminergic receptor densities

“…Up to now, the Hilus/CA4 region of the mouse hippocampus is often omitted in anatomical studies, and if presented, sometimes referred to as hilar region of the DG or included into the CA3 region, while functional studies differentiate hilar neurons from the rest of the DG (Danielson et al, 2017;Scharfman & Myers, 2012;Swaminathan, Wichert, Schmitz, & Maier, 2018;Tong et al, 2015;S. Zhao, Chai, Forster, & Frotscher, 2004).…”