Excitatory Actions of GABA after Neuronal Trauma

Abstract

GABA is the dominant inhibitory neurotransmitter in the CNS. By opening Cl Ϫ channels, GABA generally hyperpolarizes the membrane potential, decreases neuronal activity, and reduces intracellular Ca 2ϩ 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 Ca 2ϩ . Different types of trauma that were effective included neurite transection, replating, osmotic imbalance, and excess heat. The depolarizing actions of GABA after trauma increased Ca 2ϩ levels up to fourfold in some neurons, occurred in more than half of the severely injured neurons, and was long lasting (Ͼ1 week). The mechanism for the reversed action of GABA appears to be a depolarized Cl Ϫ reversal potential that results in outward rather than inward movement of Cl Ϫ , 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 Ca 2ϩ channel allows extracellular Ca 2ϩ to enter the neuron. The long-lasting capacity to raise Ca 2ϩ 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 Ca 2ϩ levels in injured cells. Furthermore, the excitatory actions of GABA after neuronal injury may contribute to maladaptive signal transmission in affected GABAergic brain circuits.

CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury

“…We used a direct spinal cord compression͞crush method (22), which resulted in SCI similar to those observed with other mechanical injury models (23)(24)(25)(26)(27) and demonstrate here, in a randomized study, a dramatic survival and recovery of walking ability in paralyzed mice after treatment with CM101. In support of our in vivo observation, we demonstrate prevention by CM101 of Wallerian degeneration of injured axons in cultured spinal cord neurons and that ␥-aminobutyrate (GABA)-mediated depolarization occurring in traumatized spinal cord neurons in culture (28,29) was reversed by CM101. Furthermore, we show that CM101 improved recovery of neuronal conductivity in traumatized cultured CNS from mice embryos.…”

In the Adult Hippocampus, Chronic Nerve Growth Factor Deprivation Shifts GABAergic Signaling from the Hyperpolarizing to the Depolarizing Direction

“…GABA, the main inhibitory transmitter in the brain, during postnatal development or in particular conditions, including epilepsy (Cohen et al, 2002;Huberfeld et al, 2007), axonal injury (Nabekura et al, 2002), trauma (van den Pol et al, 1996), neuropathic pain (Coull et al, 2005), and inflammatory hyperalgesia and allodynia (Funk et al, 2008), becomes depolarizing and excitatory. This effect depends on a reverse chloride gradient after alterations in intracellular chloride homeostasis.…”

Perturbed Chloride Homeostasis and GABAergic Signaling in Human Temporal Lobe Epilepsy

“…These changes coincide with a hyperpolarizing shift in the reversal potential of cortical pyramidal cell GABAergic responses (Ben-Ari et al, 1989;Payne et al, 2003;Farrant and Kaila, 2007). In the adult, deafferentation and trauma downregulate KCC2, decrease Cl Ϫ extrusion, and induce a depolarizing shift in GABA A receptor-mediated responses (Katchman et al, 1994;van den Pol et al, 1996;Vale and Sanes, 2000;Nabekura et al, 2002;Rivera et al, 2002;Coull et al, 2003;Topolnik et al, 2003). Furthermore, both KCC2 and NKCC1 are highly regulated by phosphorylation and other post-transcriptional mechanisms (Russell, 2000;Balakrishnan et al, 2003;Vale et al, 2003;Khirug et al, 2005;Blaesse et al, 2006;de Los Heros et al, 2006).…”