title: Anxiety- and depression-like phenotype of hph-1 mice deficient in tetrahydrobiopterin.
abstract: Decreased tetrahydrobiopterin (BH4) biosynthesis has been implicated in the pathophysiology of anxiety and depression. The aim of this study was therefore to characterise the phenotype of homozygous hph-1 (hph) mice, a model of BH4 deficiency, in behavioural tests of anxiety and depression as well as determine hippocampal monoamine and plasma nitric oxide levels. In the elevated zero maze test, hph mice displayed increased anxiety-like responses compared to wild-type mice, while the marble burying test revealed decreased anxiety-like behaviour. This was particularly observed in male mice. In the tail suspension test, hph mice of both sexes displayed increased depression-like behaviours compared to wild-type counterparts, whereas the forced swim test showed a trend towards increased depression-like behaviours in male hph mice, but significant decrease in depression-like behaviours in female mice. This study provides the first evidence that congenital BH4 deficiency regulates anxiety- and depression-like behaviours. The altered responses observed possibly reflect decreased hippocampal serotonin and dopamine found in hph mice compared to wild-type mice, but also reduced nitric oxide formation. We propose that the hph-1 mouse may be a novel tool to investigate the role of BH4 deficiency in anxiety and depression.
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark. Electronic address: Arafat.Nasser@regionh.dk.
authors.forename: Arafat
authors.initials: A
authors.lastname: Nasser
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors.forename: Lisbeth B
authors.initials: LB
authors.lastname: Møller
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jess H
authors.initials: JH
authors.lastname: Olesen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen
authors.forename: Louise
authors.initials: L
authors.lastname: Konradsen Refsgaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
authors.forename: Louise S
authors.initials: LS
authors.lastname: Konradsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
authors.forename: Jesper T
authors.initials: JT
authors.lastname: Andreasen
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics*; D015306:Biogenic Monoamines / Q000032:analysis; D003863:Depression / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D009569:Nitric Oxide / Q000097:blood; D010641:Phenotype; D010661:Phenylketonurias / Q000235:genetics* / Q000523:psychology*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000502:physiology*; D012737:Sex Factors
chemical_list: D015306:Biogenic Monoamines; C103827:Phc1 protein, mouse; D009569:Nitric Oxide; D063150:Polycomb Repressive Complex 1
keywords: Anxiety; Depression; Dopamine; GCH1; Nitric oxide; Serotonin