title: Neuropeptide Y Y1 receptor hippocampal overexpression via viral vectors is associated with modest anxiolytic-like and proconvulsant effects in mice.
abstract: Neuropeptide Y (NPY) exerts anxiolytic- and antidepressant-like effects in rodents that appear to be mediated via Y1 receptors. Gene therapy using recombinant viral vectors to induce overexpression of NPY in the hippocampus or amygdala has previously been shown to confer anxiolytic-like effect in rodents. The present study explored an alternative and more specific approach: overexpression of Y1 receptors. Using a recombinant adeno-associated viral vector (rAAV) encoding the Y1 gene (rAAV-Y1), we, for the first time, induced overexpression of functional transgene Y1 receptors in the hippocampus of adult mice and tested the animals in anxiety- and depression-like behavior. Hippocampal Y1 receptors have been suggested to mediate seizure-promoting effect, so the effects of rAAV-induced Y1 receptor overexpression were also tested in kainate-induced seizures. Y1 receptor transgene overexpression was found to be associated with modest anxiolytic-like effect in the open field and elevated plus maze tests, but no effect was seen on depression-like behavior using the tail suspension and forced swim tests. However, the rAAV-Y1 vector modestly aggravated kainate-induced seizures. These data indicate that rAAV-induced overexpression of Y1 receptors in the hippocampus could confer anxiolytic-like effect accompanied by a moderate proconvulsant adverse effect. Further studies are clearly needed to determine whether Y1 gene therapy might have a future role in the treatment of anxiety disorders.
authors.affiliation: Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and Protein Laboratory, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: M V
authors.initials: MV
authors.lastname: Olesen
authors.forename: S H
authors.initials: SH
authors.lastname: Christiansen
authors.forename: C R
authors.initials: CR
authors.lastname: Gøtzsche
authors.forename: L
authors.initials: L
authors.lastname: Nikitidou
authors.forename: M
authors.initials: M
authors.lastname: Kokaia
authors.forename: D P D
authors.initials: DP
authors.lastname: Woldbye
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D003292:Convulsants / Q000008:administration & dosage* / Q000633:toxicity; D000229:Dependovirus / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000633:toxicity; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D017476:Receptors, Neuropeptide Y / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012640:Seizures / Q000235:genetics / Q000378:metabolism* / Q000821:virology
chemical_list: D014151:Anti-Anxiety Agents; D003292:Convulsants; C507698:Npy1r protein, mouse; D017476:Receptors, Neuropeptide Y; D011993:Recombinant Fusion Proteins