Depaulis A, Deransart C, Vergnes M, Marescaux C
Unité INSERM n(o) 398, Faculté de Médecine, Strasbourg.
Rev Neurol (Paris). 1997;153 Suppl 1:S8-13.
Generalized epileptic seizures are underlied by specific circuits where GABAergic synapses are involved at different levels. The role of these synapses depends on (i) the type of epilepsy and (ii) their localization within the central nervous system. This dual complexity can be illustrated by two examples from animal experimentation. Clinical, as well as experimental data have shown that the neural mechanisms underlying generalized non-convulsive seizures (e.g., absence-epilepsy) are distinct from those involved in convulsive generalized seizures. Pharmacological reactivity to anti-epileptic compounds is different between these two forms of seizures. Hippocampus and amygdala are key-structures in convulsive seizures whereas they are not involved in absence-epilepsy. A thalamo-cortical circuit generates the spike-and-wave discharges in absence epilepsy. Global activation of GABAergic transmission by systemic administration generally suppresses convulsive seizures whereas it aggravates absence in both humans and animals. Further investigations using a genetic model of absence seizures in the rat have suggested that this aggravation may be related to the role of post-synaptic GABA-B receptors in slow hyperpolarization, in the relay nuclei of the thalamus. By "de-inactivating" low-threshold calcium currents, activation of these receptors facilitates rhythmic activity in the thalamo-cortical circuit. In addition, regulation of transmitter release by presynaptic GABA-B receptors in the thalamus and the cortex may also contribute to the control of absence seizures. A blockade of the GABA-B receptors, either locally in the thalamus or systemically suppresses absence seizures. The critical role of the substantia nigra in the control of different forms of seizures has been demonstrated recently in the 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 the superior colliculus were shown to suppress both convulsive and non-convulsive seizures. This circuitry involving the basal ganglia may exert a "remote inhibitory control" over generalized epilepsies generated in other areas. In conclusion, the pharmacological manipulation of GABAergic transmission has different consequences on epilepsy depending on the form of seizures and the connections and functions of the GABAergic neurons in a given structure. The design of new therapeutical tools based on the manipulation of GABAergic mechanisms in the central nervous system requires to take into account this neuroanatomical dimension.
全身性癫痫发作由特定的神经回路引起，其中GABA能突触在不同水平上参与其中。这些突触的作用取决于：（i）癫痫的类型；（ii）它们在中枢神经系统中的定位。动物实验中的两个例子可以说明这种双重复杂性。临床以及实验数据表明，全身性非惊厥性癫痫发作（例如失神癫痫）的神经机制与惊厥性全身性癫痫发作所涉及的机制不同。这两种癫痫发作形式对抗癫痫化合物的药理反应性不同。海马体和杏仁核是惊厥性癫痫发作的关键结构，而它们不参与失神癫痫。在失神癫痫中，丘脑 - 皮质回路会产生棘波和慢波放电。全身给药导致GABA能传递的整体激活通常会抑制惊厥性癫痫发作，而在人类和动物中都会加重失神发作。使用大鼠失神癫痫的遗传模型进行的进一步研究表明，这种加重可能与丘脑中继核中突触后GABA - B受体在缓慢超极化中的作用有关。通过“去失活”低阈值钙电流，这些受体的激活促进了丘脑 - 皮质回路中的节律性活动。此外，丘脑和皮质中突触前GABA - B受体对递质释放的调节也可能有助于控制失神发作。在丘脑局部或全身阻断GABA - B受体可抑制失神发作。最近在大鼠中已证明黑质在控制不同形式癫痫发作中的关键作用。该结构是大脑中GABA能终末、神经元和受体最丰富的区域之一。在中脑上丘局部应用GABA模拟物导致其靶神经元去抑制，已显示可抑制惊厥性和非惊厥性癫痫发作。这种涉及基底神经节的神经回路可能对其他区域产生的全身性癫痫发挥“远程抑制控制”作用。总之，根据癫痫发作的形式以及给定结构中GABA能神经元的连接和功能，对GABA能传递进行药理操作对癫痫有不同的影响。基于对中枢神经系统中GABA能机制的操作设计新的治疗工具需要考虑到这种神经解剖学维度。
