Bipolar disorder is a devastating illness that is marked by recurrent episodes of mania and depression. There is growing evidence that the disease is correlated with disruptions in synaptic plasticity cascades involved in cognition and mood regulation. Alleviating the symptoms of bipolar disorder involves chronic treatment with mood stabilizers like lithium or valproate. These two structurally dissimilar drugs are known to alter prominent signaling cascades in the hippocampus, but their effects on the postsynaptic density complex remain undefined. In this work, we utilized mass spectrometry to identify and measure levels of proteins from the rat hippocampal postsynaptic density (PSD). Our data show that in response to chronic treatment of mood stabilizers, there were no gross qualitative changes but rather subtle quantitative perturbations in PSD proteins linked to several key signaling pathways. Our data specifically support the changes in actin dynamics induced by chronic valproate treatment, suggesting that the drug induces structural changes in the synaptic zone. The neuronal protein called BH3-interacting domain death agonist (Bid) is member of the B-cell lymphoma-2 (Bcl-2) protein family of proteins involved in programmed cell death and apoptosis. Previous studies have shown that psychological stress reduces levels of Bcl-2 in brain regions implicated in the pathophysiology of mood disorders, whereas antidepressants and mood stabilizers increase Bcl-2 levels in these brain regions. The Bcl-2 protein family has an essential role in cellular resilience as well as synaptic and neuronal plasticity and may influence mood and affective behaviors. This study inhibited Bid activity in mice using two pharmacological antagonists BI-11A7 and BI-2A7. These agents were studied in several well-known rodent behavioral tests used to assess depression-like states: the forced swim test, the tail suspension test, the learned helplessness paradigm, and the female urine-sniffing test. BI-11A7 significantly reduced depressive-like behaviors in the tests. Learned helplessness induction increased the activation of apoptosis-inducing factor (AIF), a mitochondrial cell-death molecule activated by Bid;in contrast, AIF expression was attenuated by chronic BI-11A7 infusion. The results suggest that functional perturbation of apoptotic proteins such as Bid is a potential target for developing novel therapeutics for mood disorders. Altered muscarinic acetylcholine receptor levels and receptor-coupled signaling processes have been associated with mood disorders. M1, one of five muscarinic receptor subtypes, couples to the phospholipase C/protein kinase C (PLC/PKC) and extracellular signal-regulated kinase (ERK) pathways. Mood stabilizers regulate these pathways. MicroRNAs (miRNAs) are small noncoding RNAs that suppress translation in a sequence-selective manner. Lithium downregulates several miRNAs, including let-7b and let-7c. One predicted target of let-7b and let-7c is the M1 receptor. We hypothesized that miRNAs regulate M1 receptor levels, and that disrupted M1 gene translation leads to disrupted downstream signaling pathways and aberrant behaviors that are rescued by lithium treatment. In one study, the effects of miRNAs and chronic treatment with mood stabilizers on M1 levels were measured in primary neuronal cell cultures and in rat frontal cortex. In addition, effects of chronic treatment with mood stabilizers on several signaling cascades and M1-modulated behaviors were examined in wild-type and M1 knockout mice. We found that let-7b but not let-7c negatively regulated M1 levels. Chronic treatment with lithium, but not valproate, increased M1 levels in the rat cortex. M1 knockout mice exhibited ERK pathway deficits and behavioral hyperactivity;chronic treatment with lithium attenuated these deficits and hyperactivity. We concluded that lithium treatment can affect M1 receptor function through intracellular signaling enhancement and concomitant receptor upregulation via mechanisms involving miRNAs. Muscarinic dysfunction may contribute to mood disorders, while M1 receptors and the downstream ERK pathway may serve as potential therapeutic targets for alleviating manic symptoms such as psychomotor hyperactivity.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
U.S. National Institute of Mental Health
Zip Code
Malkesman, O; Austin, D R; Tragon, T et al. (2012) Targeting the BH3-interacting domain death agonist to develop mechanistically unique antidepressants. Mol Psychiatry 17:770-80
Nanavati, Dhaval; Austin, Daniel R; Catapano, Lisa A et al. (2011) The effects of chronic treatment with mood stabilizers on the rat hippocampal post-synaptic density proteome. J Neurochem 119:617-29
Creson, Thomas K; Austin, Daniel R; Shaltiel, Galit et al. (2011) Lithium treatment attenuates muscarinic M(1) receptor dysfunction. Bipolar Disord 13:238-49
Hunsberger, Joshua G; Machado-Vieira, Rodrigo; Austin, Daniel R et al. (2011) Bax inhibitor 1, a modulator of calcium homeostasis, confers affective resilience. Brain Res 1403:19-27
Chen, Guang; Henter, Ioline D; Manji, Husseini K (2010) Presynaptic glutamatergic dysfunction in bipolar disorder. Biol Psychiatry 67:1007-9
Yuan, Peixiong; Zhou, Rulun; Wang, Yun et al. (2010) Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia. J Affect Disord 124:164-9
Chen, G; Henter, I D; Manji, H K (2010) Translational research in bipolar disorder: emerging insights from genetically based models. Mol Psychiatry 15:883-95
Fan, Teresa W-M; Yuan, Peixiong; Lane, Andrew N et al. (2010) Stable isotope-resolved metabolomic analysis of lithium effects on glial-neuronal metabolism and interactions. Metabolomics 6:165-179
Hunsberger, Joshua G; Austin, Daniel R; Chen, Guang et al. (2009) Cellular mechanisms underlying affective resiliency: the role of glucocorticoid receptor- and mitochondrially-mediated plasticity. Brain Res 1293:76-84
Zhou, Rulun; Yuan, Peixiong; Wang, Yun et al. (2009) Evidence for selective microRNAs and their effectors as common long-term targets for the actions of mood stabilizers. Neuropsychopharmacology 34:1395-405

Showing the most recent 10 out of 20 publications