title: Differential effects of rapamycin treatment on tonic and phasic GABAergic inhibition in dentate granule cells after focal brain injury in mice.
abstract: The cascade of events leading to post-traumatic epilepsy (PTE) after traumatic brain injury (TBI) remains unclear. Altered inhibition in the hippocampal formation and dentate gyrus is a hallmark of several neurological disorders, including TBI and PTE. Inhibitory synaptic signaling in the hippocampus is predominately driven by γ-aminobutyric acid (GABA) neurotransmission, and is prominently mediated by postsynaptic type A GABA receptors (GABAAR's). Subsets of these receptors involved in tonic inhibition of neuronal membranes serve a fundamental role in maintenance of inhibitory state, and GABAAR-mediated tonic inhibition is altered functionally in animal models of both TBI and epilepsy. In this study, we assessed the effect of mTOR inhibition on hippocampal hilar inhibitory interneuron loss and synaptic and tonic GABAergic inhibition of dentate gyrus granule cells (DGCs) after controlled cortical impact (CCI) to determine if mTOR activation after TBI modulates GABAAR function. Hilar inhibitory interneuron density was significantly reduced 72h after CCI injury in the dorsal two-thirds of the hemisphere ipsilateral to injury compared with the contralateral hemisphere and sham controls. Rapamycin treatment did not alter this reduction in cell density. Synaptic and tonic current measurements made in DGCs at both 1-2 and 8-13weeks post-injury indicated reduced synaptic inhibition and THIP-induced tonic current density in DGCs ipsilateral to CCI injury at both time points post-injury, with no change in resting tonic GABAAR-mediated currents. Rapamycin treatment did not alter the reduced synaptic inhibition observed in ipsilateral DGCs 1-2weeks post-CCI injury, but further reduced synaptic inhibition of ipsilateral DGCs at 8-13weeks post-injury. The reduction in THIP-induced tonic current after injury, however, was prevented by rapamycin treatment at both time points. Rapamycin treatment thus differentially modifies CCI-induced changes in synaptic and tonic GABAAR-mediated currents in DGCs.
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, United States.
authors.forename: Corwin R
authors.initials: CR
authors.lastname: Butler
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, United States; Epilepsy Center, University of Kentucky, Lexington, KY 40536, United States; Center for Advanced Translational Stroke Science, University of Kentucky, Lexington, KY 40536, United States.
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Boychuk
authors.affiliation: Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536, United States; Epilepsy Center, University of Kentucky, Lexington, KY 40536, United States; Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 40536, United States. Electronic address: bret.smith@uky.edu.
authors.forename: Bret N
authors.initials: BN
authors.lastname: Smith
mesh_terms: D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000473:pathology*; D018891:Dentate Gyrus / Q000473:pathology*; D004195:Disease Models, Animal; D007839:Functional Laterality / Q000187:drug effects / Q000235:genetics; D018682:GABA Agents / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects*; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000777:Anesthetics; D018682:GABA Agents; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D049452:Green Fluorescent Proteins; D019893:Ribosomal Protein S6 Kinases; D005968:Glutamate Decarboxylase; C015542:gaboxadol; D020123:Sirolimus
keywords: Controlled cortical impact; Dentate gyrus; Hippocampus; Inhibition; Synapse; Tonic current; mTOR; γ-Aminobutyric acid receptors