Injury to the developing brain during the time of cortical neuronal migration induces malformation and aberrant cortical lamination. Focal ischemic damage caused by maternal infections, trauma, or vascular disease specifically reduces the malformation of microgyria. This malformation is associated with mental retardation, schizophrenia, dyslexia, developmental delay and epilepsy. Seizures often occur after a substantial lag period relative to the time of injury and are among the most intractable. Most, but not all patients have recurring seizures, and remission is achieved In only a small subset of these patients. Identifying the source of this variability is likely to aid in the evolution of novel prevention and treatment therapies. The goal of this proposal is to identify mechanisms that contribute to the sudden onset and selective spontaneous emission of epileptogenesis associated with microgyria. The hypothesis that the focal loss of a specific group of neurons promotes aberrant development of cortical afferent connections and prevents remission will be tested. Because brain development in ferrets is immature at birth, deletion of selective cellular laminae can be achieved. In addition, the expanded postnatal development of the ferret will allow for greater temporal specificity in manipulations intended to prevent onset of epileptiform cortical hyperexcitability. We propose the following three Specific Aims: 1.To determine in a ferret model of microgyria whether the proportion of animals showing epileptiform activity and emission is correlated with a) the proportion of layer IV neurons retained within the malformation, and b) the degree of thalamocortical rearrangement. This will be conducted using a combination of electrophysiological field potential recordings with an in vitro slice preparation and anatomical tract tracing methods. 2. To identify the functional result to the neurons of the epileptogenic zone of altering the amount of layer IV persisting within the malformation. These experiments involve visualized whole-cell patch-clamp recordings of excitatory and inhibitory synaptic currents. 3. To determine whether a spatially and temporally focal blockade of activity will prevent or delay the onset of epileptogenesis. Applying tetrodotoxin in an Elvax polymer to the cortical surface prior to onset will test this idea. The long-term goals of this project are to distinguish anatomical and physiological contributions to epileptogenesis and developmental delay that may lead to unique prevention therapies such as transplantation of particular cell types.
|Zsombok, A; Jacobs, K M (2007) Postsynaptic currents prior to onset of epileptiform activity in rat microgyria. J Neurophysiol 98:178-86|