The research in the Section on Molecular Neurobiology focuses on mechanisms of actions of mood stabilizers, notably lithium and valproic acid (VPA). The central hypothesis is that lithium and VPA, by inhibiting glycogen synthase kinase-3 (GSK-3) and histone deacetylases (HDACs), respectively, induce neuroprotection, neurotrophism, anti-inflammation, neurogenesis, angiogenesis, cell migration and behavioral benefits. In the current year, we have made remarkable progress in these areas using cellular and animal disease models. Dr. Zhifei Wang discovered that post-ischemic treatment with VPA robustly attenuated blood-brain barrier (BBB) breakdown and brain edema in a rat cerebral ischemia model of stroke, the second leading cause of death in the US (Wang et al., 2011a,b). BBB protection by VPA involves HDAC inhibition-mediated suppression of nuclear factor-kappaB activation, matrix metalloproteinase-9 (MMP-9) induction, and tight junction degradation. Her ongoing research showed that post-ischemic chronic VPA treatment markedly improved rotarod performance of ischemic rats and enhanced angiogenesis in the ischemic cortex. This enhanced angiogenesis by VPA was associated with up-regulation of HIF-1alpha, MMP-9 and vesicular endothelial growth factor (VEGF). A recent in vitro study conducted by Dr. Li-Kai Tsai in the Section indicated that lithium and VPA stimulated mesenchymal stem cell (MSC) migration through distinct targets and mediators: GSK-3beta-MMP-9 and HDAC-CXC chemokine receptor 4 (CXCR4), respectively (Tsai et al., 2010). In a follow-up in vivo study Dr. Wang in conjunction with Dr. Tsai primed MSCs with lithium and/or VPA which were then injected into ischemic rats 24 hrs after ischemic onset. This increased the number of MSCs homing to the cerebral infarcted regions such as the cortex and striatum two weeks after transplantation (Tsai et al., 2011). Transplanted MSCs co-primed with lithium and VPA exerted additive homing/migrating capacity, reduced infarct volume and promoted functional recovery. Our results suggest the potential utility of MSCs primed with mood stabilizers for the treatment of brain disorders. Traumatic brain injury (TBI) has been recognized as one of the leading causes of death in the young population. However, there is currently no known treatment to mitigate its damaging effects. Dr. Fengshan Yu in collaboration with Dr. Yumin Zhang of USUHS has evaluated whether lithium could improve outcome following TBI. Mice first underwent controlled cortical impact injury, and were then injected with a 1.5 mEq/kg dose of lithium 15 min after injury and once daily thereafter for up to two weeks. Lithium treatment reduced TBI-induced lesion volume and neurodegeneration (Yu et al., 2011). Lithium also markedly improved motor coordination in a beam-walk test and significantly reduced TBI-induced anxiety-like behavior in an open-field test. Additionally, lithium robustly increased serine phosphorylation of GSK-3beta, suggesting that the underlying protective mechanisms are triggered by increased phosphorylation of this kinase to inhibit its activity. Dr. Chi-Tso Chiu in conjunction with Guangping Liu and Peter Leeds has investigated effects of lithium and VPA in two transgenic mouse models of Huntington's disease (HD), a fatal genetic disorder. We demonstrated that treatment with lithium and VPA robustly prevented motor deficits and normalized psychiatric symptoms in these two HD mouse lines, YAC128 and N171-82Q (Chiu et al., 2011a, b). In both transgenic mouse models, co-treatment with lithium and VPA was more effective than mono-therapy with either drug. Importantly, combined lithium and VPA treatment prolonged the lifespan of N171-82Q mice. Further, this combined treatment consistently inhibited GSK-3beta and HDACs, and caused sustained BDNF and HSP70 elevation in mouse brains, suggesting that these two molecules are critical for the execution of behavioral benefits (Chiu et al., 2011a). Dr. Chiu is also a key investigator demonstrating that injection of lentiviral GSK-3beta shRNA into the dentate gyrus induced antidepressant-like behaviors in chronically stressed mice, indicating that GSK-3 activation in this hippocampal sub-region is involved in stress-induced depressive-like behavior (Omata et al., 2011). His ongoing studies will involve in-depth investigation of the effects of drug treatments on cognitive function, and potential molecular mechanisms such as microRNA regulation in mediating these beneficial effects in HD mice. Additionally, Dr. Chiu, is the primary investigator in a new project studying the effect of long-term lithium pretreatment on acute ketamine-induced antidepressant-like-effect in a mouse model of stress. Dr. Joshua Hunsberger is particularly interested in studying microRNAs (miRNAs), small non-protein coding RNAs, as potential targets for treating mood disorders. Working with Emily Fessler and Fairouz Chibane, he has used an established glutamate excitotoxicity model of primary neuronal cultures to identify miRNAs regulated following glutamate exposure in the absence or presence of mood stabilizers (lithium, VPA and/or in combination). He is currently evaluating the function of key miRNA candidates and identifying downstream mRNA targets. In another project, he is determining which miRNAs may facilitate the benefits of lithium and VPA in a rat cerebral ischemia model and validating miRNAs that may illuminate novel neuroprotective mechanisms to treat ischemia. Finally, Dr. Hunsberger is working on two projects to evaluate miRNAs as potential biomarkers for bipolar illness. In the first approach, he is using a rat model to profile miRNAs regulated by lithium in prefrontal cortex, hippocampus, lymphocytes, and plasma. He hopes to identify unique brain and peripheral miRNA profiles based on tissue identity as well as lithium treatment. He is also using immortalized lymphoblasts from controls and bipolar patients (either lithium responders or non-responders) to determine miRNA expression under baseline conditions and following lithium treatment. He anticipates that these experiments will yield miRNA profiles identifying patients that respond either poorly or effectively to lithium treatment. Dr. Yan Leng has continued to investigate molecular mechanisms underlying the synergistic neuroprotective effects of combined lithium-VPA treatment against glutamate excitotoxicity in primary cerebellar neurons. She has demonstrated that fibroblast growth factor 21 (FGF21) was selectively and robustly induced in aging cerebellar neurons treated with lithium and VPA, while single treatment with either drug was ineffective. Knockdown of overexpressed FGF21 with its shRNA largely blocked the neuroprotective effects of lithium-VPA co-treatment. Further, exogenous FGF21 activated the cell survival Akt signaling pathway and protected against glutamate excitotoxicity. These experiments provide evidence that FGF21 is one of the factors synergistically induced by lithium-VPA co-treatment and contributes to neuroprotection. In another study, Dr. Leng has launched an investigation on the neurobiology of lamotrigine, which was recently approved by the FDA for treating bipolar disorder. Her results demonstrated that lamotrigine is an indirect inhibitor of HDACs and a robust neuroprotectant in primary neurons. The protective mechanisms can be attributed to epigenetic upregulation of cytoprotective Bcl-2 through enhanced histone acetylation at the histone promoter to increase its transcription. In addition, lamotrigine at a subeffective concentration produced synergistic protective effects with lithium. Thus, neuroprotection is a common feature for all three FDA-approved mood stabilizers.

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Leng, Yan; Wang, Junyu; Wang, Zhifei et al. (2016) Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3. Int J Neuropsychopharmacol 19:
Linares, Gabriel R; Chiu, Chi-Tso; Scheuing, Lisa et al. (2016) Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington's disease. Exp Neurol 281:81-92
Hunsberger, J G; Chibane, F L; Elkahloun, A G et al. (2015) Novel integrative genomic tool for interrogating lithium response in bipolar disorder. Transl Psychiatry 5:e504
Leng, Y; Wang, Z; Tsai, L-K et al. (2015) FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers. Mol Psychiatry 20:215-23
Chiu, Chi-Tso; Scheuing, Lisa; Liu, Guangping et al. (2015) The mood stabilizer lithium potentiates the antidepressant-like effects and ameliorates oxidative stress induced by acute ketamine in a mouse model of stress. Int J Neuropsychopharmacol 18:
Leeds, Peter R; Yu, Fengshan; Wang, Zhifei et al. (2014) A New Avenue for Lithium: Intervention in Traumatic Brain Injury. ACS Chem Neurosci :
Kim, Hyeon Ju; Chuang, De-Maw (2014) HDAC inhibitors mitigate ischemia-induced oligodendrocyte damage: potential roles of oligodendrogenesis, VEGF, and anti-inflammation. Am J Transl Res 6:206-23
Scheuing, Lisa; Chiu, Chi-Tso; Liao, Hsiao-Mei et al. (2014) Preclinical and clinical investigations of mood stabilizers for Huntington's disease: what have we learned? Int J Biol Sci 10:1024-38
Lee, Jiunn-Tay; Chou, Chung-Hsing; Cho, Nai-Yu et al. (2014) Post-insult valproate treatment potentially improved functional recovery in patients with acute middle cerebral artery infarction. Am J Transl Res 6:820-30
Huang, Fengzhen; Zhang, Li; Long, Zhe et al. (2014) miR-25 alleviates polyQ-mediated cytotoxicity by silencing ATXN3. FEBS Lett 588:4791-8

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