Enduring changes in tonic GABAA receptor signaling in dentate granule cells after controlled cortical impact brain injury in mice

Exp Neurol. 2016 Mar;277:178-189. doi: 10.1016/j.expneurol.2016.01.005. Epub 2016 Jan 6.

Abstract

Changes in functional GABAAR signaling in hippocampus have previously been evaluated using pre-clinical animal models of either diffuse brain injury or extreme focal brain injury that precludes measurement of cells located ipsilateral to injury. As a result, there is little information about the status of functional GABAAR signaling in dentate granule cells (DGCs) located ipsilateral to focal brain injury, where significant cellular changes have been documented. We used whole-cell patch-clamp recordings from hippocampal slices to measure changes in GABAARs in dentate granule cells (DGCs) at 1-2, 3-5, and 8-13 weeks after controlled cortical impact (CCI) brain injury. Synaptic and tonic GABAAR currents (ITonicGABA) were measured in DGCs at baseline conditions and during application of the GABAAR agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol hydrochloride (THIP) to assess in the function of δ subunit-containing GABAARs. DGCs ipsilateral to CCI exhibited no changes in the amplitude of resting ITonicGABA relative to DGCs after sham-injury or contralateral to CCI. In contrast, there was a significant reduction in the THIP-evoked ITonicGABA in DGCs ipsilateral to CCI at both time-points. Tonic GABAergic inhibition of DGCs ipsilateral to injury also exhibited reduced responsiveness to the neurosteroid THDOC. ITonicGABA in DGCs ipsilateral to CCI did not exhibit a change in sensitivity to L655,708, an inverse agonist with selectivity for α5 subunit-containing GABAARs, suggesting a lack of functional change in GABAARs containing this subunit. At the 8-13 week time-point, gene expression of GABAAR subunits expected to contribute to ITonicGABA (i.e., α4, α5 and δ) was not significantly altered by CCI injury in isolated dentate gyrus. Collectively, these results demonstrate enduring functional changes in ITonicGABA in DGCs ipsilateral to focal brain injury that occur independent of altered gene expression.

Keywords: Controlled cortical impact; GABA(A) receptors; Post-traumatic epilepsy; Tonic GABA current; Traumatic brain injury.

Publication types

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

MeSH terms

  • Anesthetics / pharmacology
  • Animals
  • Brain Injuries / pathology*
  • Cerebral Cortex / pathology*
  • Dentate Gyrus / pathology*
  • Desoxycorticosterone / analogs & derivatives
  • Desoxycorticosterone / pharmacology
  • Disease Models, Animal
  • Electric Stimulation
  • Functional Laterality / drug effects
  • GABA Agonists / pharmacology
  • Gene Expression Regulation / drug effects
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Isoxazoles / pharmacology
  • Male
  • Mice
  • Neurons / metabolism*
  • RNA, Messenger / metabolism
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Signal Transduction / physiology*

Substances

  • Anesthetics
  • GABA Agonists
  • Imidazoles
  • Isoxazoles
  • L 655,708
  • RNA, Messenger
  • Receptors, GABA-A
  • Desoxycorticosterone
  • tetrahydrodeoxycorticosterone
  • gaboxadol