Canine and Feline Epilepsy. Luisa De Risio
acidification increased neuronal excitability and resulted in after-discharges following each spike, and in seizure-like discharges. The investigators hypothesized that the intracellular acidification reduced excitability by reducing gap-junction function. Application of octanol, a nonspecific gap junction blocker, abolished spontaneous interictal spiking (de Curtis et al., 1998).
Glial buffering of glutamate
Glial uptake of perisynaptic glutamate is the major mechanism forestalling accumulation of glutamate at the synapse (Benarroch, 2005). Astrocytes have an equally important role in the regulation of extracellular potassium. Astrocytic buffering of potassium maintains extracellular levels below a ceiling of 12 mM (Benarroch, 2005). In some cases, such as the epileptic brain, glia may also release glutamate, thereby prolonging post-synaptic excitation. Tian et al. (2005) recently showed that glial release of glutamate contributed to the maintenance of the paroxysmal depolarizing shift that is the hallmark of ‘epileptic’ neurons. Failure of glia to buffer extracellular glutamate, let alone glutamate release from glia, can be expected to result in prolonged excitatory drive and seizure maintenance.
Increased GABA-ergic inhibition
A basic mechanism to control focal seizure activity is GABA-ergic synaptic inhibition mediated by local interneurons. Seizure discharges within the seizure onset zone produce recurrent inhibition within the seizure initiation zone, thus reducing excitatory output (Kostopoulos et al., 1983; Dorn and Witte, 1995). Early investigations of the spike and wave components of ‘spike-wave’ discharges showed that the spike component is associated with a burst of rapid action-potential firing, while the wave component is associated with a pause in action-potential firing (Dichter and Spencer, 1969). The pause in neuronal firing results from synaptic inhibition produced by local inhibitory inter-neurons activated by the volley of excitatory activity comprising the ‘spike’ component, an example of feedback inhibition. Feed-forward inhibition is a fundamental feature of cortical processing (Swadlow, 2003). Feed-forward inhibition may also play an important role; an interneuron activated by a principal cell sends inhibitory signals to principal cells outside the focus, inhibiting the propagation of the seizure (Trevelyan et al., 2007). Recent evidence indicates that a principal cell axon may synapse on the presynaptic terminal of an inhibitory interneuron, bypassing somatic activation of the interneuron altogether by causing transmitter release directly from the inhibitory synaptic terminal (Connors and Cruikshank, 2007).
Synaptic inhibition is mediated by the presynaptic release of the neurotransmitter GABA, which acts on the postsynaptic neuron via receptors located on the soma, dendrites, or presynaptic terminals. GABA receptors are present in two major varieties, GABAA and GABAB. GABAB receptors are metabotropic acting through G-protein second messengers. The pre- and postsynaptic distribution of GABAB receptors, along with mixed evidence of anti- and proconvulsant effects of GABAB activation, makes it difficult to determine their role in seizure termination (Chen et al., 2004). GABAA receptors are chloride-conducting membrane channels that open rapidly in response to GABA. Desensitization of GABAA receptors during status epilepticus likely contributes to the failure of seizure termination (Chen et al., 2007). Desensitization of GABAA receptors is also the basis of the loss of efficacy of benzodiazepine medications used to treat status epilepticus. Multiple mechanisms appear to contribute to GABAA receptor desensitization. Increased internalization of GABAA receptors during status epilepticus reduces the effect of GABA-ergic stimulation (Goodkin et al., 2007). Changes in subunit composition may also contribute to GABAA receptor desensitization, although this process acts over many minutes to hours, and appears to affect long-term neuronal excitability and epileptogenesis rather than seizure termination. Nonsynaptic GABAA receptors, in contrast, do not desensitize and instead are capable of tonic inhibition, which produces long-lasting changes in neuronal reactivity. These tonic GABA receptors typically contain particular subunits – delta and possibly gamma – that alter the properties of the receptors (Richerson, 2004). Tonic receptors are activated by micromolar levels of the extra-synaptic GABA, which arrives either by diffusion from a synapse before reuptake, or by release into the extracellular space via non-synaptic mechanisms. Tonic GABA receptors may play an important role in epilepsy. On the one hand, reduction of tonic GABA currents (as produced experimentally by a mutation in the delta-subunit of tonic GABA receptors) is associated with generalized epilepsy. On the other hand, progesterone-derived neurosteroids enhance tonic GABA currents, and may play a role in preventing seizure genesis, and potentially in terminating ongoing seizures (Stell et al., 2003). It is also clear that the contribution of extrasynaptic GABAA receptors changes during maturation, and may contribute to changes in seizure susceptibility during development.
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