Cortical malformations are commonly associated with medically-intractable epilepsies. A clear understanding of the role of such malformations in aberrant neural activity could provide insights for the treatment of these poorly managed disorders. This proposal will use a genetic animal model of a human cortical malformation, subcortical band heterotopia (SBH; or double cortex), in which large bilateral heterotopia are associated with spontaneous recurrent seizures. The rat model, termed """"""""tish"""""""", provides unique opportunities for investigating both the development of malformations and mechanisms of epilepsy. Preliminary electrophysiological studies indicate that inhibitory GABAergic synaptic transmission is disturbed in the tish rat neocortex. Based on these observations, we hypothesize that altered inhibitory synaptic activity in the tish cortex predisposes the brain to seizures.
Specific Aim 1 will characterize GABAergic synaptic inhibition in the tish rat neocortex using whole-cell patch clamp recording techniques in acute brain slices of the tish neocortex. It is important to note that GABAA receptors (GABAAR) undergo maturational changes in subunit composition during cortical development, and it is possible that this normal developmental process is disturbed in the tish cortex. Experiments will therefore be undertaken at multiple developmental time points during which key changes in GABAAR composition and function are known to occur.
Specific Aim 2 will identify alterations in GABAAR subunits/subtypes, and GABA transporters in the developing and adult tish neocortex. Changes in these molecular substrates can affect the functional characteristics of GABAergic transmission, and any observed changes will be compared with the electrophysiological features defined in Aim 1. Together, these studies will elucidate fundamental features of a key inhibitory system in a dysplastic, seizure-prone brain.
| Trotter, Stacey A; Kapur, Jaideep; Anzivino, Matthew J et al. (2006) GABAergic synaptic inhibition is reduced before seizure onset in a genetic model of cortical malformation. J Neurosci 26:10756-67 |
