Role of Neuropeptides and Neurotrophic Factors in Seizure Modulation

University dissertation from Avtandil Nanobashvili, Section of Restorative Neurology, WNC, BMC A11, 221 84 Lund

Abstract: The presented thesis explores role of glial cell line derived neurotrophic factor family receptor a2 (GFRa2), as well as neuropeptide Y (NPY) and galanin and their receptors in modulation of seizure activity. We demonstrate that mice lacking the GFRa2 gene (GFRa2-/-) exhibit suppressed seizure generalization in traditional and rapid kindling models. We suggest that impaired basal excitatory transmission at medial perforant path granule cell synapses, detected in these animals might partly account for the observed deficit in the kindling development. Moreover, GFRa2-/- mice exhibit impaired persistence of kindling epilepsy following traditional kindling, which is associated with the lack of seizure-induced downregulation of NPY immunoreactivity in hilar interneurons. It is conceivable that alterations in NPY signaling in GFRa2-/- mice could lead to the above-mentioned impaired maintenance of abnormal excitability. We also demonstrate that rapidly recurring seizures evoke cell- and region-specific, differential regulation of genes for NPY and its receptors (Y1, Y2 and Y5) in widespread areas of the rat limbic system. Moreover, using recently developed highly selective Y5 receptor agonist and antagonist, we show that activation of this receptor dampens spontaneous (interictaform) bursting in the CA3 region of rat hippocampal slices. Our studies demonstrating that NPY exerts inhibitory effect on spontaneous epileptiform activity in the entorhinal cortex further strengthen the concept of NPY as a widespread regulator of epileptic activity in the brain. Using galanin overexpressing mice, we show that ectopically expressed galanin in cortical and hippocampal neurons is regulated by seizures, is released during high frequency neuronal activity, and suppresses kindling epileptogenesis by interacting with presynaptic galanin receptors and decreasing glutamate release.

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