Malformations of cortical development (MCD) are often associated with developmental delay, cognitive deficit and intractable epilepsy. Despite considerable effort, our understanding of synaptic function - a key component mediating these neurological symptoms - within a malformation remains limited. To investigate this issue, we study injury- and genetically-based animal models of MCD, as well as human tissue resected from epilepsy patients with MCD. Based on prior investigations, we focus this proposal on our overall hypothesis that aberrant network activity underlies cognitive dysfunction and seizures associated with a brain malformation. Here, our studies focus on mice with a heterozygous inactivation of LIS1 (Lis1) e.g., a genetically-based MCD model exhibiting seizures, severe disorganization of hippocampal architecture and enlarged ventricles. Preliminary data suggest a significant enhancement of excitatory synaptic transmission onto CA1 pyramidal neurons in disorganized regions of Lis1 mice. Because enhanced excitation appears to be associated with a striking increase in synaptic facilitation and vesicle density, studies are proposed to examine presynaptic mechanisms in Lis1 mice. Techniques will involve use of acute hippocampal slices maintained in vitro, and application of visualized patch clamp methods to study the physiological function of pyramidal neurons and granule cells within a disorganized hippocampus. Pharmacological and genetic manipulations will be made to assess presynaptic release mechanisms and potential pre-clinical treatment strategies. Video- EEG monitoring and immunohistochemistry techniques will also be applied.
Three specific aims are proposed: (i) to further examine enhanced excitatory neurotransmission in Lis1 mice, (ii) to examine the function of newborn granule cells in Lis1 mice, and (iii) to examine synaptic function and neurogenesis in a conditional Lis1 mouse. Our studies are designed to elucidate mechanisms contributing to epileptogenesis in a malformed brain. Results of the proposed experiments could have translational impact on the development of new therapies for patients with MCD.
Epilepsy is a common neurological disorder afflicting nearly 3 million Americans. Malformations of cortical development are one potential mechanism resulting in the emergence of epilepsy, cognitive deficit and developmental delay in children. Using a mouse mutant lacking a gene associated with a malformation of cortical development first identified in humans, we will examine mechanisms contributing to seizure generation and potential avenues for treatment.
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