Neuropeptide Y-Stimulated [ 35 S]GTPcS Functional Binding is Reduced in the Hippocampus After Kainate-Induced Seizures in Mice HEIDI ELBRØND-BEK, 1,2 JANNE DAMM OLLING, 2 CASPER R. GØTZSCHE, 1,2 ALISON WATERFIELD, 2 GITTA W € ORTWEIN, 2 AND DAVID P.D. WOLDBYE 1,2 * 1 Department of Neuroscience and Pharmacology, Laboratory of Neural Plasticity, University of Copenhagen, Copenhagen, Denmark 2 Department of Neuroscience and Pharmacology, Laboratory of Neuropsychiatry, University of Copenhagen, Copenhagen, Denmark KEY WORDS [ 35 S]GTPgS autoradiography; kainate-induced seizures; functional binding; neuropeptide Y receptors ABSTRACT Kainate-induced seizures constitute a model of temporal lobe epilepsy where prominent changes are observed in the hippocampal neuropeptide Y (NPY) sys- tem. However, little is known about the functional state and signal transduction of the NPY receptor population resulting from kainate exposure. Thus, in this study, we explored functional NPY receptor activity in the mouse hippocampus and neocortex after kainate-induced seizures using NPY-stimulated [ 35 S]GTPgS binding. Moreover, we also studied levels of [ 125 I]-peptide YY (PYY) binding and NPY, Y1, Y2, and Y5 receptor mRNA in these kainate-treated mice. Functional NPY binding was unchanged up to 12 h post-kainate, but decreased significantly in all hippocampal regions after 24 h and 1 week. Similarly, a decrease in [ 125 I]-PYY binding was found in the dentate gyrus (DG) 1 week post-kainate. However, at 2 h, 6 h, and 12 h, [ 125 I]-PYY binding was increased in all regions, and in the CA1 also at 24 h post-kainate. NPY mRNA levels were promi- nently increased in hippocampal regions, reaching maximum at 12 and 24 h. Y1 and Y5 mRNA levels were lowered in the DG at 24 and 2 h, respectively, while Y2 mRNA levels were elevated at 24 h in the DG and CA3. This study confirms rat kainate studies by showing pronounced adaptive changes in the mouse hippocampus both with regard to NPY synthesis and NPY receptor synthesis and binding, which may contribute to regu- lating neuronal seizure susceptibility after kainate. However, the potential seizure- suppressant effects of increased NPY gene expression at late time points post-kainate could be attenuated by the novel finding of reduced NPY-receptor G-protein activation.- Synapse 00:000–000, 2014. V C 2014 Wiley Periodicals, Inc. INTRODUCTION Temporal lobe epilepsy is a common type of epi- lepsy, frequently originating in the hippocampal for- mation (Yilmazer-Hanke et al., 2000). Since a substantial group of patients remains resistant to medical treatment, there is still a great need to understand the processes regulating temporal lobe seizures that might lead to improvement of treatment outcome. Neuropeptide Y (NPY) is a 36-amino acid peptide with an abundant and widespread expression in the central nervous system, including the hippo- campal formation (Redrobe et al., 1999). The hippo- campal NPY system undergoes substantial adaptive changes in response to chemically and electrically induced seizures (Vezzani and Sperk, 2004; Vezzani et al., 1999). It is widely believed that these changes play an important role in regulating neuronal excit- ability during seizures. Consistent with this concept, Contract grant sponsor: Danish Research Council for Health and Disease; Con- tract grant number: 64750; Contract grant sponsor: Lundbeck Foundation; Con- tract grant sponsor: Foundation of Doctor Sofus Carl Emil Friis and His Wife Olga Doris Friis; Contract grant sponsor: Elsass Foundation; Contract grant sponsor: Master Joiner Sophus Jacobsen and His Wife Astrid Jacobsen’s Foun- dation; Contract grant sponsor: Frimodt-Heineke Foundation; Contract grant sponsor: Aase and Ejnar Danielsen’s Foundation; Contract grant sponsor: Ivan Nielsen Foundation; Contract grant sponsor: Danish Research Foundation. *Correspondence to: David P.D. Woldbye, Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, Symbion, 3 Fruebjergvej, DK-2100, Copenhagen, Denmark. E-mail: woldbye@sund.ku.dk Received 9 April 2014; Revised 16 June 2014; Accepted 26 June 2014 DOI: 10.1002/syn.21762 Published online 1 July 2014 in Wiley Online Library (wileyonlinelibrary. com). Ó 2014 WILEY PERIODICALS, INC. SYNAPSE 00:00–00 (2014)