Potentiation of GABA(A) currents after mechanical injury of cortical neurons.
Numerous studies have implicated glutamate receptors, glutamate neurotoxicity, and hyperexcitation in the pathobiology of traumatic brain injury, yet much less is known about the effects of neurotrauma on inhibitory GABA channels of the brain. Using an in vitro cell injury model, we tested whether mild stretch injury altered the GABA(A) currents of cultured rat cortical neurons. The application of 1-100 microM GABA to single pyramidal neurons voltage clamped to -60 mV activated an inward current that reversed near 0 mV in solutions containing symmetrical [Cl-]. This current was inhibited by bicuculline, consistent with mediation by GABA(A) receptor channels. In injured neurons, 50 microM GABA elicited a peak current density of 41.2 +/- 2.6 pA/pF (n = 82), which was significantly larger than in uninjured control neurons, 20.2 +/- 1.7 pA/pF (n = 69, p < 0.01). The GABA(A) currents of injured neurons did not differ from those of control neurons in their sensitivity to GABA or their reversal potentials, suggesting that GABA current potentiation did not result from changes in the agonist affinity or ionic selectivity of the channels. GABA current potentiation was prevented by injuring neurons in the presence of the NMDA antagonist APV, or the CaMKII inhibitor KN93. These results thus suggest that NMDA receptor activation following neuronal injury may potentiate GABA(A) channels through the activation of CaMKII. The increase in GABA(A) receptor function observed following injury could potentially contribute to dysfunctional synaptic function and information processing as well as unconsciousness and coma following human brain trauma.
Kao
Chang-Qing
CQ
Virginia Commonwealth University Medical Center, Richmond, Virginia.
Goforth
Paulette B
PB
Ellis
Earl F
EF
Satin
Leslie S
LS
D000818:Animals; D018929:Cell Culture Techniques; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D019579:Neocortex / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D013314:Stress, Mechanical; D009435:Synaptic Transmission / Q000502:physiology*
D011963:Receptors, GABA-A