Excitatory actions of GABA after neuronal trauma

GABA is the dominant inhibitory neurotransmitter in the CNS. By opening Cl^- channels, GABA generally hyperpolarizes the membrane potential, decreases neuronal activity, and reduces intracellular Ca²⁺ of mature neurons. In the present experiment, we show that after neuronal trauma, GABA, both synaptically released and exogenously applied, exerted a novel and opposite effect, depolarizing neurons and increasing intracellular Ca²⁺. Different types of trauma that were effective included neurite transection, replating, osmotic imbalance, and excess heat. The depolarizing actions of GABA after trauma increased Ca²⁺ levels up to fourfold in some neurons, occurred in more than half of the severely injured neurons, and was long lasting (>1 week). The mechanism for the reversed action of GABA appears to be a depolarized Cl^- reversal potential that results in outward rather than inward movement of Cl^-, as revealed by gramicidin-perforated whole-cell patch-clamp recording. The consequent depolarization and resultant activation of the nimodipine sensitive L- and conotoxin-sensitive N-type voltage- activated Ca²⁺ channel allows extracellular Ca²⁺ to enter the neuron. The long-lasting capacity to raise Ca²⁺ may give GABA a greater role during recovery from trauma in modulating gene expression, and directing and enhancing outgrowth of regenerating neurites. On the negative side, by its depolarizing actions, GABA could increase neuronal damage by raising cytosolic Ca²⁺ levels in injured cells. Furthermore, the excitatory actions of GABA after neuronal injury may contribute to maladaptive signal transmission in affected GABAergic brain circuits.