Lithium Enhances Synaptic Plasticity: Implication for Treatment of Bipolar Disorder

Abstract

Although lithium has remained as the drug of choice in the treatment of bipolar disorder over the past 50 years, the mechanism by which it exerts its therapeutic effects is not well understood. A large body of evidence from molecular, cellular and clinical studies proposes that lithium have positive actions in enhancing neuroplasticity and synaptic plasticity, and these actions are associated with its efficacy in the treatment of bipolar disorder and other psychiatric disorders (Manji et al. 1999; Manji and Duman 2001; Rowe and Chuang 2004; Tsaltas et al. 2009). Lithium modulates intracellular signal transduction pathways involved in the activation of transcription factors (PEBP-2β, P53, and CREB) and the gene expression of diverse neurotrophic and neuroprotective factors (Chalecka-Franaszek and Chuang 1999; Grimes and Jope 2001; Jope and Roh 2006; Manji et al. 1999; Manji and Duman 2001). Among these factors, brain derived neurotrophic factor (BDNF), B-cell CLL/lymphoma 2 (Bcl-2) and cyclic adenosine monophosphate response element-binding protein (CREB) have been the most extensively studied (Angelucci et al. 2003; Chuang et al. 2002; Fukumoto et al. 2001; Manji and Chen 2002). It is well known that BDNF, Bcl-2 and CREB play important roles in maintaining normal synaptic plasticity in diverse ways (Adams and Cory 1998; McAllister et al. 1999; ; Shaywitz and Greenberg 1999; Silva et al. 1998). Evidence from brain imaging and postmortem studies and studies with animal models suggests that in patients with bipolar disorder, diverse pathological changes in neuroplastic processes lead to impairment in synaptic communications in neuronal circuits involved in the pathophysiology of bipolar disorder. Lithium may enhance synaptic plasticity and thereby restore normal synaptic communications in the circuits by up-regulating neurotrophic and neuroprotective factor such as BDNF, Bcl-2 and activating CREB, the major transcription factor of gene expression of BDNF and Bcl-2, and this action may be associated with the efficacy of the drug. However, this theory has been developed primarily based on molecular biological and clinical studies. This theory has never been fully tested by directly examining the effects of lithium exposure on synaptic plasticity. Only few studies have specifically focused on the effects of lithium exposure on synaptic plasticity.