GABAERGIC MECHANISMS IN PARTIAL EPILEPSIE S

The gamma-aminobutyric acid (GABA) is one of the most important inhibi tory transmitter in the CNS. When GABA is released in the synaptic cle ft, it can act on two types of receptors, type A (GABA(A)-R) and type B. The GABA(A)-R is an ionotropic receptor whose subunits form a chlor ide channel. It contains specific binding sites at least for GABA, ben zodiazepines, picrotoxin, barbiturates, anesthetic steroids, divalent cations such as Zn2+ and other compounds. Neurotransmitters and neurop eptides that regulate intracellular second messengers may modulate the responses of GABA(A)-R in the post-synaptic membrane and thus affect the synaptic plasticity. While consensus sites for several kinases are present on many subunit-subtypes, the functional consequences of thes e phosphorylations are unclear. However, the maintenance of normal GAB A currents required the activity of a unique kinase specific for the G ABA(A)-R. This intracellular regulation site might be involved in syna ptic plasticity and considered as a site of vulnerability for epilepto genesis. The generation of epileptic discharge, synchronized burst fir ing and interictal spikes, can be subsequent to the alteration of GABA (A)-R function. A consequence of GABAergic disinhibition is the format ion of new polysynaptic pathways leading to a network of neurons that were previously not connected. Cell loss and plasticity are currently observed in most patients with temporal lobe epilepsy: CA1 pyramidal c ells are missing and messy fibers of dentate granule cells project bac k through the granule cell layer to form recurrent terminals on granul e cell dendrites. This messy fiber sprouting leads to the destruction of most dentate hilar somatostatine interneurons. Nevertheless, local circuit neurons containing glutamic acid decarboxylase survive in this layer and in all regions of the sclerotic hippocampus. A decrease of the GABA release has been proposed as a basis for disinhibition tempor al-labs epilepsy is partially characterized by a loss of glutamate-sti mulated GABA release that is secondary to a reduction in the number of GABA transporters. A molecular reorganization of GABA(A)-R subunits h as been suggested in the kindling model of temporal lobe epilepsy beca use the zinc released from abberantly sprouted messy fiber terminals i s responsible for a collapse of augmented inhibition by GABA. These re sults support the concept of a loss of inhibition in chronic epilepsy models and probably in human epilepsies.