Increase of GABAA receptor-mediated tonic inhibition in dentate granule cells after traumatic brain injury

Neurobiol Dis. 2010 Jun;38(3):464-75. doi: 10.1016/j.nbd.2010.03.012. Epub 2010 Mar 18.


Traumatic brain injury (TBI) can result in altered inhibitory neurotransmission, hippocampal dysfunction, and cognitive impairments. GABAergic spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) and tonic (extrasynaptic) whole cell currents were recorded in control rat hippocampal dentate granule cells (DGCs) and at 90days after controlled cortical impact (CCI). At 34 degrees C, in CCI DGCs, sIPSC frequency and amplitude were unchanged, whereas mIPSC frequency was decreased (3.10+/-0.84Hz, n=16, and 2.44+/-0.67Hz, n=7, p<0.05). At 23 degrees C, 300nM diazepam increased peak amplitude of mIPSCs in control and CCI DGCs, but the increase was 20% higher in control (26.81+/-2.2pA and 42.60+/-1.22pA, n=9, p=0.031) compared to CCI DGCs (33.46+/-2.98pA and 46.13+/-1.09pA, n=10, p=0.047). At 34 degrees C, diazepam did not prolong decay time constants (6.59+/-0.12ms and 6.62+/-0.98ms, n=9, p=0.12), the latter suggesting that CCI resulted in benzodiazepine-insensitive pharmacology in synaptic GABA(A) receptors (GABA(A)Rs). In CCI DGCs, peak amplitude of mIPSCs was inhibited by 100microM furosemide (51.30+/-0.80pA at baseline and 43.50+/-5.30pA after furosemide, n=5, p<0.001), a noncompetitive antagonist of GABA(A)Rs with an enhanced affinity to alpha4 subunit-containing receptors. Potentiation of tonic current by the GABA(A)R delta subunit-preferring competitive agonist THIP (1 and 3microM) was increased in CCI DGCs (47% and 198%) compared to control DGCs (13% and 162%), suggesting the presence of larger tonic current in CCI DGCs; THIP (1microM) had no effect on mIPSCs. Taken together, these results demonstrate alterations in synaptic and extrasynaptic GABA(A)Rs in DGCs following CCI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Injuries / physiopathology*
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / physiopathology*
  • Diazepam / pharmacology
  • Furosemide / pharmacology
  • GABA Agonists / pharmacology
  • GABA Modulators / pharmacology
  • GABA-A Receptor Agonists
  • GABA-A Receptor Antagonists
  • Hippocampus / drug effects
  • Hippocampus / physiopathology
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology
  • Isoxazoles / pharmacology
  • Male
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology*
  • Neurons / drug effects
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / metabolism*
  • Synapses / drug effects
  • Synapses / physiology
  • Temperature
  • Time Factors


  • GABA Agonists
  • GABA Modulators
  • GABA-A Receptor Agonists
  • GABA-A Receptor Antagonists
  • Isoxazoles
  • Receptors, GABA-A
  • Furosemide
  • gaboxadol
  • Diazepam