Glia-Neuron Interactions: Neurosteroids and Epileptogenesis

Excerpt

Glia can influence the outcome of an epileptogenic insult by controlling the recovery of neuronal networks and functions. In particular, glia may facilitate the establishment of epilepsy by impaired removal of glutamate from synapses or by releasing inflammatory cytokines and excitatory neurotransmitters, such as interleukin-1β or, respectively, glutamate, aspartate and D-serine. Opposed to these pro-excitatory/pro-epileptogenic mediators, glia can also release molecules that restrain neuronal excitability such as neurosteroids, which are potent modulators of inhibitory currents dependent on gamma-aminobutyric acid (GABA) type A receptors. In normal conditions, neurosteroids are mainly synthesized in neurons by conversion of cholesterol to pregnenolone, a step catalyzed by the cytochrome P450 cholesterol-side chain cleavage enzyme (P450scc). Following an epileptogenic insult, astrocytes transform into reactive cells and express high levels of P450scc, thus becoming major players in neurosteroid synthesis. In this context, we found that the degree of P450scc expression in astrocytes dictates the duration of the latent period. In line with this view, inhibition of neurosteroid synthesis anticipates the establishment of chronic epilepsy only when the P450scc induction is intense and long lasting. Thus, we hypothesize that reactive astrocytes may dampen neuronal excitability in the course of epileptogenesis through neurosteroid-mediated mechanisms that likely enhance GABAergic neurotransmission.