Temporal Characterization of Behavioral and Hippocampal Dysfunction in the YAC128 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a genetic neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms. Emerging evidence suggests that emotional and cognitive deficits seen in HD may be related to hippocampal dysfunction. We used the YAC128 HD mouse model to perform a temporal characterization of the behavioral and hippocampal dysfunctions. Early and late symptomatic YAC128 mice exhibited depressive-like behavior, as demonstrated by increased immobility times in the Tail Suspension Test. In addition, YAC128 mice exhibited cognitive deficits in the Swimming T-maze Test during the late symptomatic stage. Except for a reduction in basal mitochondrial respiration, no significant deficits in the mitochondrial respiratory rates were observed in the hippocampus of late symptomatic YAC128 mice. In agreement, YAC128 animals did not present robust alterations in mitochondrial ultrastructural morphology. However, light and electron microscopy analysis revealed the presence of dark neurons characterized by the intense staining of granule cell bodies and shrunken nuclei and cytoplasm in the hippocampal dentate gyrus (DG) of late symptomatic YAC128 mice. Furthermore, structural alterations in the rough endoplasmic reticulum and Golgi apparatus were detected in the hippocampal DG of YAC128 mice by electron microscopy. These results clearly show a degenerative process in the hippocampal DG in late symptomatic YAC128 animals.

Protective Effects of Agmatine Against Corticosterone-Induced Impairment on Hippocampal mTOR Signaling and Cell Death.

Chronic treatment with agmatine, similarly to fluoxetine, may cause antidepressant-like effects mediated, at least in part, by the modulation of hippocampal plasticity. However, the ability of chronic treatment with agmatine to cause antidepressant-like effects associated with the modulation of mammalian target of rapamycin (mTOR) signaling pathway and protection against neuronal death remains to be established. In this study, we investigated the effects of agmatine (0.1 mg/kg, p.o.) and the conventional antidepressant fluoxetine (10 mg/kg, p.o.) treatment on the levels of phosphorylated mTOR (p-mTOR), neuronal death, and overall volume in the hippocampal dentate gyrus (DG) of mice exposed to chronic corticosterone (20 mg/kg, p.o.) treatment for 21 days, a model of stress and depressive-like behavior. Chronic corticosterone treatment increased cell death in the sub-granular zone (SGZ) of the DG, as assessed by Fluoro-Jade B labeling. Agmatine, similarly to fluoxetine, was capable of reversing this alteration in the entire DG, an effect more evident in the ventral portion of the hippocampus. Additionally, reduced phosphorylation of mTOR (Ser2448), a pro-survival protein that is active when phosphorylated at Ser2448, was observed in the whole hippocampal DG in corticosterone-treated mice, an effect not observed in agmatine or fluoxetine-treated mice. Chronic exposure to corticosterone caused a significant reduction in overall hippocampal volume, although no alterations were observed between the groups with regards to DG volume. Altogether, the results indicate that agmatine, similar to fluoxetine, was able to counteract corticosterone-induced impairment on mTOR signaling and cell death in hippocampal DG.

Antidepressant Effects of Probucol on Early-Symptomatic YAC128 Transgenic Mice for Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HD gene, resulting in an extended polyglutamine tract in the protein huntingtin. HD is traditionally viewed as a movement disorder, but cognitive and neuropsychiatric symptoms also contribute to the clinical presentation. Depression is one of the most common psychiatric disturbances in HD, present even before manifestation of motor symptoms. Diagnosis and treatment of depression in HD-affected individuals are essential aspects of clinical management in this population, especially owing to the high risk of suicide. This study investigated whether chronic administration of the antioxidant probucol improved motor and affective symptoms as well as hippocampal neurogenic function in the YAC128 transgenic mouse model of HD during the early- to mild-symptomatic stages of disease progression. The motor performance and affective symptoms were monitored using well-validated behavioral tests in YAC128 mice and age-matched wild-type littermates at 2, 4, and 6 months of age, after 1, 3, or 5 months of treatment with probucol (30 mg/kg/day via water supplementation, starting on postnatal day 30). Endogenous markers were used to assess the effect of probucol on cell proliferation (Ki-67 and proliferation cell nuclear antigen (PCNA)) and neuronal differentiation (doublecortin (DCX)) in the hippocampal dentate gyrus (DG). Chronic treatment with probucol reduced the occurrence of depressive-like behaviors in early- and mild-symptomatic YAC128 mice. Functional improvements were not accompanied by increased progenitor cell proliferation and neuronal differentiation. Our findings provide evidence that administration of probucol may be of clinical benefit in the management of early- to mild-symptomatic HD.

Brain-Derived Neurotrophic Factor Prevents Depressive-Like Behaviors in Early-Symptomatic YAC128 Huntington's Disease Mice.

Huntington disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the Huntington disease gene. The symptomatic stage of the disease is defined by the onset of motor symptoms. However, psychiatric disturbances, including depression, are common features of HD and can occur a decade before the manifestation of motor symptoms. We used the YAC128 transgenic mice (which develop motor deficits at a later stage, allowing more time to study depressive behaviors without the confounding effects of motor impairment) to test the effects of intranasal brain-derived neurotrophic factor (BDNF) treatment for 15 days in the occurrence of depressive-like behaviors. Using multiple well-validated behavioral tests, we found that BDNF treatment alleviated anhedonic and depressive-like behaviors in the YAC128 HD mice. Furthermore, we also investigated whether the antidepressant-like effects of BDNF were associated with an increase in adult hippocampal neurogenesis. However, BDNF treatment only increased cell proliferation and neuronal differentiation in the hippocampal dentate gyrus (DG) of wild-type (WT) mice, without altering these parameters in their YAC128 counterparts. Moreover, BDNF treatment did not cause an increase in the number of dendritic branches in the hippocampal DG when compared with animals treated with vehicle. In conclusion, our results suggest that non-invasive administration of BDNF via the intranasal route may have important therapeutic potential for treating mood disturbances in early-symptomatic HD patients.