Brain malformations are characteristically associated with mental retardation, developmental delay and epilepsy. With recent advances in neuro-imaging it is now clear that cortical malformations are a common feature of therapy-resistant seizure syndromes in children. Unfortunately, our understanding of how cells located with malformations contribute to neurological dysfunction is quite limited. To address this problem, we studied a unique rodent model of malformation-associated epilepsy i.e., methylazoxymethanol (MAM) - exposed rats. In the previous grant cycle, we demonstrated defects in potassium channel function, pharmaco-resistance, and alterations in synaptic inhibition. Here we propose to continue studies in our injury-based model of cortical malformations (MAM-exposed rats) and significantly expand our research to include analysis of a genetically-based model of Type I lissencephaly (Lis-1 mutant mice). Using rodent models featuring distinct hippocampal malformations, we hope to obtain a more complete understanding of synaptic function in a malformed brain. The current proposal will focus on excitatory synapses as glutamate- mediated neurotransmission is critical to epileptogenesis and overall cognitive function. We will explore the hypothesis that malformed brain regions result in altered excitatory circuits. Techniques will involve use of hippocampal slices maintained in vitro, and application of visualized patch-clamp methods to study synaptic function. Pharmacological experiments will be performed to assess receptor function and how endogenous neurotransmitters modulate the activity of dysplastic neurons. Molecular and immunohistochemical studies will be performed on tissue from MAM and Lis-1 animals to examine expression and distribution of glutamate receptor subunits. In some studies, dual patch-clamp recording or laser-guided photo-stimulation of caged glutamate will be used to map excitatory inputs to dysplastic neurons.
Three specific aims are proposed: i) characterize glutamate-mediated currents in a malformed hippocampus, ii) identify glutamate receptor subunits in a malformed hippocampus, and iii) identify synaptic excitatory inputs to dysplastic neurons in a malformed hippocampus. The results promise to provide new information about synaptic function in a malformed brain and may lead to the design of novel anticonvulsant treatments for these otherwise intractable forms of epilepsy.
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