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

Jeffery A. Boychuk, Corwin R. Butler, Katalin Cs Halmos, Bret N. Smith

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)178-189
Number of pages12
JournalExperimental Neurology
Volume277
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

Keywords

  • Controlled cortical impact
  • GABA receptors
  • Post-traumatic epilepsy
  • Tonic GABA current
  • Traumatic brain injury

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Fingerprint Dive into the research topics of 'Enduring changes in tonic GABA<sub>A</sub> receptor signaling in dentate granule cells after controlled cortical impact brain injury in mice'. Together they form a unique fingerprint.

Cite this