Cognitive disorders and neurogenesis deficits in Huntington's disease mice are rescued by fluoxetine

Abstract

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.

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…Fluoxetine treatment (starting at 4 weeks of age) improved hippocampal-dependent cognitive function (assessed by a T-maze test) and reversed the depressive phenotype (evaluated with the Porsolt forced swim test), but had no effect on the locomotor deficits and the loss of body weight characteristic of these transgenic mice. Importantly, fluoxetine also rescued the neurogenic process in the R6/1 DG, strongly supporting the hypothesis that modulation of hippocampal neurogenesis might improve cognitive function in HD (Grote et al, 2005). In a more recent study, Peng et al (2008) tested the potential benefitial effects of another serotonine reuptake inhibitor sertraline in R6/2 mice.…”

“…Thus, Grote et al (2005) sought to investigate the effects of the antidepressant fluoxetine in R6/1 mice. Fluoxetine treatment (starting at 4 weeks of age) improved hippocampal-dependent cognitive function (assessed by a T-maze test) and reversed the depressive phenotype (evaluated with the Porsolt forced swim test), but had no effect on the locomotor deficits and the loss of body weight characteristic of these transgenic mice.…”

Reprint of Female C57BL/6 mice show consistent individual differences in spontaneous interaction with environmental enrichment that are predicted by neophobia

“…Interaction time is important: direct contact is required for enrichment to have positive effects on, for example, cortical weight [14], and experimentally increasing rodents' interaction times enhances such benefits [15,16]. Affective consequences of interaction are also probably impactful, because stress reduction is a likely mechanism by which enrichments exert their potential benefits [17,18], with increased stress, in contrast, antagonising such effects [19]. One key factor affecting the impact of enrichments is therefore likely to be the exact nature and presentation of the objects supplied.…”

Human Embryonic Stem Cells: A Resource for In Vitro Neuroscience Research?

“…Perhaps more importantly, hESCs can be used to study the processes involved in the early stages of neurodevelopment. It is already apparent that some neurodegenerative disorders may be disorders of neural development (Gokhan and Mehler, 2001) or adult cellular plasticity (van Dellen et al, 2005). Protein characteristics of disease processes, such as a-synuclein (Parkinson disease), huntingtin (Huntington's disease), and pre-senilin-1 (Alzheimer's disease), may interact with each other and normal protein partners to cause sublethal changes in cellular homeostasis.…”

“…Clearly, in genetically determined disorders, such as Huntington's disease, non-human stem cells from mouse models could be used in this manner to provide further insights into this debilitating illness. However, evidence of disrupted adult neurogenesis that can be pharmacologically ameliorated in Huntington's transgenic mice (Grote et al, 2005) suggests that modulation of adult stem cells may also be a promising therapeutic target for such neurodegenerative diseases.…”