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The Journal of Neuroscience, August 15, 2000, 20(16):6276-6281
Modulation of Hippocampal Excitability and Seizures by
Galanin
Andrey M.
Mazarati1, 4,
John G.
Hohmann6, 8,
Andrea
Bacon5,
Hantao
Liu1, 4,
Raman
Sankar2, 3,
Robert A.
Steiner6, 7, 8,
David
Wynick5, and
Claude G.
Wasterlain1, 3, 4
1 Departments of Neurology, 2 Pediatrics,
and 3 Brain Research Institute, University of California
Los Angeles, School of Medicine, Los Angeles, California 90095-1769, 4 Epilepsy Research Laboratories, Veterans Affairs,
Greater Los Angeles Healthcare System, Sepulveda, California
91343-2099, 5 Department of Medicine, Bristol University,
Bristol, BS2-8HW United Kingdom, and 6 Neurobiology and
Behavior Program and Departments of 7 Obstetrics and
Gynecology, and 8 Physiology and Biophysics, University of
Washington, Seattle, Washington 98195-7290
Previous studies have shown that the expression of the neuropeptide
galanin in the hippocampus is altered by seizures and that exogenous
administration of galanin into the hippocampus attenuates seizure
severity. To address the role of endogenous galanin in modulation of
hippocampal excitability and its possible role in seizure mechanisms,
we studied two types of transgenic mice: mice with a targeted
disruption of the galanin gene (GalKO) and mice that overexpress the
galanin gene under a dopamine- -hydroxylase promoter (GalOE). GalKO
mice showed increased propensity to develop status epilepticus after
perforant path stimulation or systemic kainic acid, as well as greater
severity of pentylenetetrazol-induced convulsions. By contrast, GalOE
mice had increased resistance to seizure induction in all three models.
Physiological tests of hippocampal excitability revealed enhanced
perforant path-dentate gyrus long-term potentiation (LTP) in GalKO and
reduced LTP in GalOE. GalKO showed increased duration of afterdischarge
(AD) evoked from the dentate gyrus by perforant path simulation,
whereas GalOE had increased threshold for AD induction.
Depolarization-induced glutamate release from hippocampal slices was
greater in GalKO and lower in GalOE, suggesting that alterations of
physiological and seizure responses in galanin transgenic animals may
be mediated through modulation of glutamate release.
Our data provide further evidence that hippocampal galanin acts as an
endogenous anticonvulsant and suggest that genetically induced changes
in galanin expression modulate both hippocampal excitability and
predisposition to epileptic seizures.
Key words:
galanin; transgenic mice; seizures; hippocampus; long-term potentiation; glutamate
Copyright © 2000 Society for Neuroscience 0270-6474/00/20166276-06$05.00/0
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