Neuronal Networks in Epilepsy: Comparative Audiogenic Seizure Networks

Abstract Neuronal networks involved in the epilepsies have been widely studied. The epilepsies are central nervous system disorders characterized by abnormal firing patterns of neurons within neuronal networks that are specific to the type of epilepsy. Critical brain sites or “hubs” within these networks and a variety of network control mechanisms have been identified in the various experimental forms of epilepsy. These epilepsy networks include models of developmental epilepsy, absence epilepsy, kindling epilepsy, status epilepticus, and generalized human epilepsy. One of the problems with much of the network-related information in these epilepsy models and human data is that the onset of the seizure is unpredictable, so the actual network nucleus (hub) for seizure initiation and the propagation pathway of the seizure through the network nuclei are uncertain. However, there are several animal models and certain forms of human epilepsy that are triggered by external (sensory) stimuli, which allows seizure onset to be under experimental control (“reflex” epilepsy). In most models of reflex epilepsy, the seizures are audiogenic seizures (AGS) that are induced by acoustic stimuli. Genetic AGS models have been studied in great detail, which allow comparisons of network hubs and mechanisms. These models include genetically epilepsy-prone rats (GEPR-9s and GEPR-3s) derived from the Sprague–Dawley strain and the Wistar-derived Strasbourg and Brazilian audiogenic rats and Russian (Krushinski–Molodkina) rats. Susceptibility to AGS can also be induced, and these models include thyroid deficiency–induced, ischemia-induced, and ethanol withdrawal–induced AGS. The induced models exhibit similar behavioral patterns of AGS, and these induced models have shed further light on the common hubs and mechanisms of AGS. AGS network elements involve the lower brainstem auditory network up through the critical hub in the inferior colliculus (IC), which projects onto other brainstem sites, including the deep layers of the superior colliculus, the pontine reticular formation, the periaqueductal gray, and the substantia nigra reticulata. Projections from these latter sites to the spinal cord generate the convulsive behaviors via overactivation of normal midbrain locomotor networks. Each of the sites plays a sequential dominant role during the behavior changes that occur during the convulsion. Glutamatergic and GABAergic mechanisms in certain of these network hubs, particularly in the IC, have been shown to be critically involved in initiating network activation. In addition, certain sites in the forebrain, including the amygdala, are differentially implicated in the different genetic AGS models. These different forms of AGS exhibit similar, but not identical, patterns of convulsive behavior, which are mediated by analogous but not identical network sites. The similarities and differences in network sites and mechanisms discovered with this comparative approach may provide a template for improved understanding of the “variations on a theme” seen in many human brain disorders that exhibit overlapping spectra of symptoms but do not display identical behavioral patterns.