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The Journal of Neuroscience, March 24, 2004, 24(12):3051-3059; doi:10.1523/JNEUROSCI.4056-03.2004

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Neurobiology of Disease
Anticonvulsant and Antiepileptogenic Effects Mediated by Adeno-Associated Virus Vector Neuropeptide Y Expression in the Rat Hippocampus

Cristina Richichi,^1 * En-Ju D. Lin,^2 * Daniela Stefanin,¹ Daniele Colella,¹ Teresa Ravizza,¹ Giuliano Grignaschi,¹ Pietro Veglianese,¹ Günther Sperk,³ Matthew J. During,² and Annamaria Vezzani¹

¹Department of Neuroscience, Mario Negri Institute for Pharmacological Research, 20157 Milan, Italy, ²Department of Molecular Medicine, The University of Auckland, Auckland 1020, New Zealand, and ³Department of Pharmacology, University of Innsbruck, 6020 Innsbruck, Austria

Neuropeptide Y (NPY) inhibits seizures in experimental models and reduces excitability in human epileptic tissue. We studied the effect of long-lasting NPY overexpression in the rat hippocampus with local application of recombinant adeno-associated viral (AAV) vectors on acute kainate seizures and kindling epileptogenesis.

Transgene expression was significantly increased by 7 d, reached maximal expression by 2 weeks, and persisted for at least 3 months. Serotype 2 AAV vector increased NPY expression in hilar interneurons, whereas the chimeric serotype 1/2 vector caused far more widespread expression, also including mossy fibers, pyramidal cells, and the subiculum. EEG seizures induced by intrahippocampal kainate were reduced by 50–75%, depending on the vector serotype, and seizure onset was markedly delayed.

In rats injected with the chimeric serotype 1/2 vector, status epilepticus was abolished, and kindling acquisition was significantly delayed. Thus, targeted NPY gene transfer provides a potential therapeutic principle for the treatment of drug-resistant partial epilepsies.

Key words: epilepsy; fascia dentata; gene; kainic acid; kindling; seizure

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Received Sep 3, 2003; revised January 19, 2004; accepted January 19, 2004.

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