Differential effects of rapamycin treatment on tonic and phasic GABAergic inhibition in dentate granule cells after focal brain injury in mice

Exp Neurol. 2016 Jun;280:30-40. doi: 10.1016/j.expneurol.2016.03.022. Epub 2016 Mar 25.

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.

Keywords: Controlled cortical impact; Dentate gyrus; Hippocampus; Inhibition; Synapse; Tonic current; mTOR; γ-Aminobutyric acid receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anesthetics / pharmacology
  • Animals
  • Brain Injuries / drug therapy
  • Brain Injuries / pathology*
  • Dentate Gyrus / pathology*
  • Disease Models, Animal
  • Functional Laterality / drug effects
  • Functional Laterality / genetics
  • GABA Agents / pharmacology
  • GABAergic Neurons / drug effects*
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Immunosuppressive Agents / pharmacology*
  • Immunosuppressive Agents / therapeutic use
  • In Vitro Techniques
  • Interneurons / drug effects
  • Isoxazoles / pharmacology
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Transgenic
  • Patch-Clamp Techniques
  • Ribosomal Protein S6 Kinases / metabolism
  • Sirolimus / pharmacology*
  • Time Factors

Substances

  • Anesthetics
  • GABA Agents
  • Immunosuppressive Agents
  • Isoxazoles
  • Green Fluorescent Proteins
  • Ribosomal Protein S6 Kinases
  • Glutamate Decarboxylase
  • gaboxadol
  • Sirolimus