Modulation of hippocampal excitability and seizures by galanin

Previous studies have shown that the expression of the neuropeptide galanin in the hippocampus is altered by seizures and that exogenous administratio n of galanin into the hippocampus attenuates seizure severity. To address t he role of endogenous galanin in modulation of hippocampal excitability and its possible role in seizure mechanisms, we studied two types of transgeni c mice: mice with a targeted disruption of the galanin gene (GalKO) and mic e that overexpress the galanin gene under a dopamine-beta-hydroxylase promo ter (GalOE). GalKO mice showed increased propensity to develop status epile pticus after perforant path stimulation or systemic kainic acid, as well as greater severity of pentylenetetrazol-induced convulsions. By contrast, Ga lOE mice had increased resistance to seizure induction in all three models. Physiological tests of hippocampal excitability revealed enhanced perforan t path-dentate gyrus long-term potentiation (LTP) in GalKO and reduced LTP in GalOE. GalKO showed increased duration of afterdischarge (AD) evoked fro m the dentate gyrus by perforant path simulation, whereas GalOE had increas ed threshold for AD induction. Depolarization-induced glutamate release fro m hippocampal slices was greater in GalKO and lower in GalOE, suggesting th at 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 ant iconvulsant and suggest that genetically induced changes in galanin express ion modulate both hippocampal excitability and predisposition to epileptic seizures.