CaMK4, a key target for treating pathogenesis of depression?

Depression is a common clinical mental disorder characterized by persistent low mood and anhedonia. Although there is strong evidence indicating that chronic stress is a major contributor to the pathogenesis of depression, its precise mechanisms and physiological effects remain unclear. Calcium/calmodulin-dependent protein kinase IV (CaMK4) is a multifunctional serine/threonine kinase that is predominantly expressed in various cell types, including lymphocytes, nerve cells, and thymocytes, and it is a crucial mediator in the regulation of gene expression through the activation of various transcription factors. It regulates cellular signaling pathways by phosphorylating downstream target proteins and is closely associated with the occurrence and development of various diseases. In recent years, an increasing number of studies have shown that CaMK4 is a core component of the Ca²⁺-calmodulin-activated signaling pathway and plays a crucial role in regulating neural development and synaptic plasticity, while impairments in these aspects are all associated with depression. Nevertheless, the exact molecular involvement of CaMK4 in the development of depression has not been determined. In this review, we summarize evidence that suggests CaMK4 plays an important role in the occurrence and development of depression. We also discuss the consequences of the dysregulation of CaMK4 signalling transduction in this disease, emphasizing its impact on hippocampal neurogenesis and synaptic plasticity. It is hoped that a comprehensive understanding of the role of CaMK4 in the pathogenesis of depression will provide knowledge to assist the development of new antidepressant drugs.