GABAERGIC MECHANISMS IN GENERALIZED EPILE PSIES - THE NEUROANATOMICALDIMENSION

Generalized epileptic seizures are underlied by specific circuits wher e GABAergic synapses are involved at different levels. The role of the se synapses depends on (i) the type of epilepsy and (ii) their localiz ation within the central nervous system. This dual complexity can be i llustrated by two examples from animal experimentation. Clinical, as w ell as experimental data have shown that the neural mechanisms underly ing generalized non-convulsive seizures (e.g., absence-epilepsy) are d istinct from those involved in convulsive generalized seizures. Pharma cological reactivity to anti-epileptic compounds is different between these two forms of seizures. Hippocampus and amygdala are key-structur es in convulsive seizures whereas they are not involved in absence-epi lepsy. A thalamo-cortical circuit generates the spike-and-wave dischar ges in absence epilepsy. Global activation of GABAergic transmission b y systemic administration generally suppresses convulsive seizures whe reas it aggravates absence in both humans and animals. Further investi gations using a genetic model of absence seizures in the rat have sugg ested that this aggravation may be related to the role of post-synapti c GABA-B receptors in slow hyperpolarization, in the relay nuclei of t he thalamus. By ''de-inactivating'' low-threshold calcium currents, ac tivation of these receptors facilitates rythmic activity in the thalam o-cortical circuit In addition, regulation of transmitter release by p resynaptic GABA-B receptors in the thalamus and the cortex may also co ntribute to the control of absence seizures. A blockade of the GABA-B receptors, either locally in the thalamus or systemically suppresses a bsence seizures. The critical role of the substantia nigra in the cont rol of different forms of seizures has been demonstrated recently In t he rat. This structure is one of the richest regions of the brain for GABAergic terminals, neurons and receptors. Local applications of GABA mimetics resulting in the desinhibition of their target neurons in th e superior colliculus were shown to suppress both convulsive and non-c onvulsive seizures. This circuitry involving the basal ganglia may exe rt a ''remote inhibitory control'' over generalized epilepsies generat ed in other areas. In conclusion, the pharmacological manipulation of GABAergic transmission has different consequences on epilepsy dependin g on the form of seizures and the connections and functions of the GAB Aergic neurons in a given structure. The design of new therapeutical t ools based on the manipulation of GABAergic mechanisms in the central nervous system requires to take into account this neuroanatomical dime nsion.