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Role of Neuropeptides and Neurotrophic Factors in Seizure Modulation

Nanobashvili, Avtandil LU (2003)
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... (More)
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. (Less)
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author
supervisor
opponent
  • Doc Simonato, Michele, Dipartimento di Medicina Clinica Sperimentale, Universit√† di Ferrara
organization
publishing date
type
Thesis
publication status
published
subject
keywords
neuropsychology, neurophysiology, brain slice, entorhinal cortex, hippocampus, galanin, glial cell line-derived neurotrophic factor, neuropeptide Y, epilepsy, kindling, Neurology, neurofysiologi, neuropsykologi, Neurologi
pages
140 pages
publisher
Avtandil Nanobashvili, Section of Restorative Neurology, WNC, BMC A11, 221 84 Lund,
defense location
Segerfalksalen WNC, Lund
defense date
2003-05-26 10:15:00
ISBN
91-628-5646-4
language
English
LU publication?
yes
additional info
Article: I. Nanobashvili A., Kokaia Z. and Lindvall O. Generalization of rapidly recurring seizures is suppressed in mice lacking glial cell line-derived neurotrophic factor family receptor a2. In press: Neuroscience, (2003). Article: II. Nanobashvili A., Airaksinen M.S., Kokaia M., Rossi J., Asztely F., Olofsdotter K., Mohapel P., Saarma M., Lindvall O. and Kokaia Z. Development and persistence of kindling epilepsy are impaired in mice lacking glial cell line-derived neurotrophic factor family receptor a2. Proc. Natl. Acad. Sci. USA, 97 (2000) 12312-12317. Article: III. Kopp J., Nanobashvili A., Kokaia Z., Lindvall O. and Hokfelt T. Differential regulation of mRNAs for neuropeptide Y and its receptor subtypes in widespread areas of the rat limbic system during kindling epileptogenesis. Mol Brain Res., 72 (1999) 17-29. Article: IV. Nanobashvili A., Woldbye D.P., Bolwig T.G. and Kokaia M. Neuropeptide Y Y5 receptors suppress in vitro spontaneous epileptiform bursting in the rat hippocampus. Submitted, (2003). Article: V. Woldbye D.P., Nanobashvili A., Husum H., Bolwig T.G. and Kokaia M. Neuropeptide Y inhibits in vitro epileptiform activity in the entorhinal cortex of mice. Neurosci. Lett., 333 (2002) 127-130. Article: VI. Kokaia M., Holmberg K., Nanobashvili A., Xu Z.Q., Kokaia Z., Lendahl U., Hilke S., Theodorsson E., Kahl U., Bartfai T., Lindvall O. and Hokfelt T. Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin. Proc. Natl. Acad. Sci. USA, 98 (2001) 14006-14011.
id
31aee0d1-bd98-4d08-b436-d79db2af10be (old id 465684)
date added to LUP
2016-04-04 12:19:36
date last changed
2018-11-21 21:10:18
@phdthesis{31aee0d1-bd98-4d08-b436-d79db2af10be,
  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.},
  author       = {Nanobashvili, Avtandil},
  isbn         = {91-628-5646-4},
  language     = {eng},
  publisher    = {Avtandil Nanobashvili, Section of Restorative Neurology, WNC, BMC A11, 221 84 Lund,},
  school       = {Lund University},
  title        = {Role of Neuropeptides and Neurotrophic Factors in Seizure Modulation},
  year         = {2003},
}