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However, unchanged levels of hippocampal phosphorylated (p) cAMP\u2010responsive element\u2010binding protein (CREB) suggested unaltered nuclear PKA activity in R6 mice. Here, we extend this finding by showing that nuclear pPKA catalytic subunit (Thr197) and pPKA substrate levels were unaltered in the hippocampus of R6\/1 mice. Phosphodiesterases (PDEs) play an important role in the regulation of PKA activity. PDE10A, a cAMP\/cGMP dual\u2010substrate PDE, was reported to be restricted to the nuclear region in nonstriatal neurons. Using cell fractionation we confirmed that PDE10A was enriched in nuclear fractions, both in wild\u2010type and R6\/1 mice hippocampus, without differences in its levels or intracellular distribution between genotypes. We next investigated whether inhibition of PDE10 with papaverine could improve cognitive function in HD mice. Papaverine treatment improved spatial and object recognition memories in R6\/1 mice, and significantly increased pGluA1 and pCREB levels in R6\/1 mice hippocampus. Papaverine likely acted through the activation of the PKA pathway as the phosphorylation level of distinct cGMP\u2010dependent kinase (cGK) substrates was not modified in either genotype. Moreover, hippocampal cAMP, but not cGMP, levels were increased after acute papaverine injection. Our results show that inhibition of PDE10 improves cognition in R6 mice, at least in part through increased GluA1 and CREB phosphorylation. Thus, PDE10 might be a good therapeutic target to improve cognitive impairment in HD. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/hipo.22128","type":"journal-article","created":{"date-parts":[[2013,4,10]],"date-time":"2013-04-10T10:50:18Z","timestamp":1365591018000},"page":"684-695","source":"Crossref","is-referenced-by-count":79,"title":["PDE10 inhibition increases GluA1 and CREB phosphorylation and improves spatial and recognition memories in a Huntington's disease mouse model"],"prefix":"10.1002","volume":"23","author":[{"given":"Albert","family":"Giralt","sequence":"first","affiliation":[{"name":"Departament de Biologia Cel\u00b7lular, Immunologia i Neuroci\u00e8ncies Facultat de Medicina, Universitat de Barcelona Barcelona Spain"},{"name":"Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS) Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Universitat de Barcelona 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