Читать книгу Canine and Feline Epilepsy - Luisa De Risio - Страница 9

Research into seizures has gravitated to mechanisms associated with synaptic transmission, because of its critical role in maintaining the balance between excitation and inhibition. As more research has identified the molecular mechanisms of synaptic transmission, it has become appreciated that defects in almost every step can lead to seizures. Glutamatergic and γ-aminobutyric acid (GABA)-ergic transmission, as the major excitatory and inhibitory transmitters of the nervous system, respectively, have been examined in great detail. It is important to point out, however, that both glutamate and GABA may not have a simple, direct relationship to seizures. One reason is that desensitization of glutamate and GABA receptors can reduce effects, depending on the time-course of exposure. In addition, there are other reasons. GABA-ergic transmission can lead to depolarization rather than hyperpolarization if the gradients responsible for ion flow through GABA receptors are altered. For example, chloride is the major ion that carries current through GABAA receptors, and it usually hyperpolarizes neurons because chloride flows into the cell from the extracellular space. However, the K+Cl− co-transporters (KCCs) that are pivotal to the chloride gradient are not constant. In development, transporter expression changes, and this has led to evidence that one of the transporters, NKCC1, may explain seizure susceptibility early in life (Dzhala et al., 2005). The relationship of glutamate to excitation may not always be simple either. One reason is that glutamatergic synapses innervate both glutamatergic neurons and GABA-ergic neurons in many neuronal systems. Exposure to glutamate could have little net effect as a result, or glutamate may paradoxically increase inhibition of principal cells because the GABA-ergic neurons typically require less depolarization by glutamate to reach threshold. It is surprisingly difficult to predict how glutamatergic or GABA-ergic modulation will influence seizure generation in vivo, given these basic characteristics of glutamatergic and GABA-ergic transmission.