Emerging role of synaptic actin-regulatory pathway in the pathophysiology of mood disorders

Mood disorders, broadly classified as major depressive disorder and bipolar disorder, are the most common and costly psychiatric disorders worldwide. The complexity and heterogeneity of mood disorders are challenges to the progress of our understanding of the pathophysiology and the development of efficient diagnostic and therapeutic approaches. Nevertheless, recent preclinical and clinical studies have provided evidence that structural and functional alterations of neuronal excitatory synapses in some cortical and limbic regions are highly associated with both pathogenesis and treatment of mood disorders. Most excitatory postsynapses in the brain are formed on tiny dendritic protrusions, called dendritic spines. The actin cytoskeleton has an important role in regulating both structure and function of dendritic spines. Thus, abnormalities in the synaptic actin-regulatory pathway could be one of the key mechanisms underlying the pathophysiology of mood disorders. In this review, we highlight animal model studies demonstrating that changes in the expression or activity of proteins involved in the actin-regulatory pathway such as Rac1, Shank3, and nArgBP2 mediate the pathogenesis of depression- or manic-like behaviors. Based on these studies, we propose a hypothesis that the decrease and increase in activity of actin-regulatory pathway and the level of synaptic actin cytoskeleton in some brain regions could be an important mood regulating factor that might lead to depression and mania, respectively.