Neuronal networks in the genetically epilepsy-prone rat.

It is now possible to develop a dynamic neuronal network model for generalized convulsive seizures because of in vivo data recently obtained in a naturally occurring epilepsy model--the genetically epilepsy-prone rats (GEPR-9s). GEPR-9s exhibit audiogenic seizures (AGS) that consist of a sequence of discrete behavioral phases (i.e., wild running, clonus-tonus, and post-ictal depression). The neuronal firing changes in most nuclei implicated in the network during each phase of AGS in behaving GEPR-9s have been examined. The inferior colliculus is critical in AGS initiation, because extensive firing increases in inferior colliculus are observed preceding seizure initiation. The deep layers of superior colliculus (DLSC) are crucial to wild running, based on the emergence of tonic firing of DLSC neurons just preceding this phase. The pontine reticular nucleus (PRF) and periaqueductal gray (PAG) are critical to the clonic-tonic phase, because tonic firing patterns appear in these neurons just prior to this phase. During post-ictal depression all areas except the PRF are quiescent. These temporal relationships suggest that each nucleus plays a specific hierarchic role in each discrete convulsive behavior. Generalized tonic-clonic seizure behavior observed in human epilepsy, in GEPR-9s, and in other seizure models is likely to involve similar neuronal network components. The neurotransmitter mechanisms subserving the abnormal neuronal responses in the GEPR-9 neuronal network involve an increased availability of glutamate and a decrease in the effectiveness of gamma-aminobutyric acid (GABA) in many brain regions. Focal modification of the effects of GABA, glutamate, norepinephrine, or serotonin also modulates the nuclei of the network differentially. Together, these data reveal the anatomic, neurotransmitter, and neurophysiologic mechanisms of the neuronal network hierarchy in GEPR-9s, which is currently the most completely developed of any generalized convulsive model. Differential effects of anticonvulsants on the AGS phases and concomitant differential modifications of neuronal firing are observed on neurons in these network nuclei. With nearly complete identification of the network nuclei, the differential effects of these anticonvulsant drugs on different aspects of neuronal firing in different brain sites indicate that this experimental approach can likely identify the most sensitive therapeutic target for these agents. This concept is potentially vital to developing the most selective treatment of different convulsive behaviors occurring in human epilepsy. The neuronal network for AGS does not require brain structures rostral to the midbrain for seizure expression. However, the forebrain is recruited into an expanded seizure network through AGS repetition ("kindling"), resulting in prolonged AGS, post-tonic clonus, and epileptiform electrographic cortical abnormalities. AGS kindling produces network expansion into medial geniculate body (MGB) and amygdala and involves neuronal firing increases in MGB.