Combined treatment with the mood stabilizers lithium and valproate produces multiple beneficial effects in transgenic mouse models of Huntington’s disease

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIMH	NEURO/BEHAV/SENSYS-7

* FARE Award Winner

Authors

• CT Chiu
• G Liu
• P Leeds
• DM Chuang

Abstract

Emerging evidence suggests that lithium and valproate (VPA) have broad neuroprotective and neurotrophic properties, and that these occur via inhibition of GSK-3 and HDACs, respectively. Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by impaired movement, cognitive and psychiatric disturbances, and premature death. We treated N171-82Q and YAC128 mice, two mouse models of HD varying in genetic backgrounds and pathological progressions, with a diet containing lithium, VPA, or both. Untreated, these mice displayed a decrease in GSK-3β Ser9 phosphorylation and histone H3 acetylation in the striatum and cerebral cortex, indicating a hyperactivity of GSK-3β and HDACs. Combined treatment with lithium and VPA effectively alleviated locomotor deficits and depressive-like behaviors in both models. Furthermore, co-treatment successfully improved motor skill learning and coordination in N171-82Q, and suppressed anxiety-like behaviors in YAC128. This combined treatment consistently inhibited GSK-3β and HDACs, and caused a sustained elevation in striatal as well as cortical BDNF and HSP70. Importantly, co-treatment markedly prolonged survival of N171-82Q mice. Given that there is presently no proven treatment for HD, our results suggest that combined treatment with lithium and VPA, two mood stabilizers with a long history of safe use in humans, may have important therapeutic potential for HD patients.

back to top