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.

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

“…Y2 has predominantly presynaptic localization while Y1 and Y5 reside on postsynaptic neurons [70] possibly with different excitatory or inhibitory nature. Y1 receptor overexpression aggravated kainate-induced seizures [71] while Y5 receptor overexpression together with NPY overexpression had stronger seizure-suppressant effect than NPY overexpression alone [72]. In addition, mice lacking the Y5 receptor had enhanced sensitivity for kainateinduced seizures [73].…”

Anxiolytic-like effects after vector-mediated overexpression of neuropeptide Y in the amygdala and hippocampus of mice

“…Mice were tested in the elevated plus maze placed 50 cm above the floor in the centre of a darkened room with 4 × 60 W incandescent light bulbs placed in each corner of the room (Olesen et al, 2012a). One mouse was tested at a time for the duration of 10 min.…”

“…Mice were tested in the open field (Olesen et al, 2012a;Schmidt et al, 2011) placed in the centre of a darkened room with 4 × 60 W incandescent light bulbs placed in each corner of the room. Four mice were tested at a time in four separate open fields, each the size of 40 × 40 × 80 cm.…”

“…Thus, in the amygdala, anxiolytic-like effects have been shown following Herpes simplex (Primeaux et al, 2005) and Sindbis (Thorsell et al, 2007) viral vector-induced NPY overexpression in rats. Mouse studies have shown that recombinant adeno-associated viral (rAAV) vector-induced overexpression of NPY or Y1 receptors, but not Y5 receptors, also confers anxiolytic-like effect in the hippocampus (Lin et al, 2010;Olesen et al, 2012aOlesen et al, , 2012b. Robust reciprocal connections have been shown between the amygdala and hippocampus in the rat (Pitkänen et al, 2000).…”

Neuropeptide Y-stimulated [35S]GTPγs functional binding is reduced in the hippocampus after kainate-induced seizures in mice

“…In the brain, NPY mediates its effects predominantly via three G i -protein coupled receptors (Y1, Y2, and Y5) that participate in modulating seizures (Redrobe et al, 1999;Xapelli et al, 2006). Y1 receptors in the dentate gyrus (DG) appear to exert seizure-promoting effects (Benmaamar et al, 2003;Olesen et al, 2012) while particularly Y2, but also Y5, receptors mediate seizure-suppressant effects in the hippocampus (Baraban, 2002;El Bahh et al, 2005;Gïtzsche et al, 2012;Marsh et al, 1999;Vezzani et al, 1999;Woldbye et al, 1997Woldbye et al, , 2005Woldbye et al, , 2010.…”