Cognitive disorders and neurogenesis deficits in Huntington's disease mice are rescued by fluoxetine.
Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat encoding an extended polyglutamine tract in the huntingtin protein. Affected individuals display progressive motor, cognitive and psychiatric symptoms (including depression), leading to terminal decline. Given that transgenic HD mice have decreased hippocampal cell proliferation and that a deficit in neurogenesis has been postulated as an underlying cause of depression, we hypothesized that decreased hippocampal neurogenesis contributes to depressive symptoms and cognitive decline in HD. Fluoxetine, a serotonin-reuptake inhibitor commonly prescribed for the treatment of depression, is known to increase neurogenesis in the dentate gyrus of wild-type mouse hippocampus. Here we show that hippocampal-dependent cognitive and depressive-like behavioural symptoms occur in HD mice, and that the administration of fluoxetine produces a marked improvement in these deficits. Furthermore, fluoxetine was found to rescue deficits of neurogenesis and volume loss in the dentate gyrus of HD mice.
Grote
Helen E
HE
Howard Florey Institute, University of Melbourne, Parkville, VIC 3010, Australia. helen.grote@magd.ox.ac.uk
Bull
Natalie D
ND
Howard
Monique L
ML
van Dellen
Anton
A
Blakemore
Colin
C
Bartlett
Perry F
PF
Hannan
Anthony J
AJ
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D018891:Dentate Gyrus / Q000166:cytology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000627:therapeutic use*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects*; D009687:Nuclear Proteins / Q000235:genetics; D045442:Rotarod Performance Test / Q000379:methods; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D019680:Trinucleotide Repeat Expansion
D005473:Fluoxetine; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C086055:HTT protein, human