Roles of non-receptor tyrosine kinases in pathogenesis and treatment of depression

Abstract

Major depressive disorder is a chronic psychiatric disease with a high prevalence. Brain mechanisms for depression at cellular and molecular levels are far from clear. Increasing evidence from clinical and preclinical studies reveals critical roles of the non-receptor tyrosine kinase (nRTK) superfamily in the pathophysiology, symptomatology, and therapy of depression. To date, several nRTK members from three nRTK subfamilies, i.e., the Src family kinase (SFK), the Janus tyrosine kinase (JAK) and the focal adhesion kinase (FAK) subfamilies, may connect to the intracellular, intranuclear, and synaptic signaling network linking chronic stress to depression-and anxiety-like behavior. These SFK/JAK/FAK nRTKs are abundantly expressed in the prefrontal cortex and hippocampus, two core limbic regions implicated in depression, and are enriched at synaptic sites. In various acute or chronic animal models of depression, the nRTKs were significantly altered (up-or downregulated) in their phosphorylation, expression, subcellular/subsynaptic distribution, and/or function. Stress that precipitates depressive behavior also in luenced the interaction of nRTKs with other signaling molecules and downstream substrates, including ionotropic and metabotropic glutamate receptors. The commonly-used antidepressants showed the ability to alter nRTK activity. In sum, the limbic SFK/JAK/FAK nRTKs are sensitive to stress and undergo drastic adaptations in response to chronic depression. These long-lasting adaptations contribute to the remodeling of signaling network or synaptic plasticity critical for the vulnerability to depression and the therapeutic e ficacy of antidepressants.

Regulation of Src family kinases by muscarinic acetylcholine receptors in heterologous cells and neurons

“…Moreover, the mACh-SFK coupling in the hippocampus and striatum is thought to be critical for maintaining normal memory, cognitive behavior, mood, and movement. Dysfunction of this coupling is linked to pathogenesis of various neuropsychiatric and neurological illnesses ( Ge et al, 2020 ; Guglietti et al, 2021 ; Rajani et al, 2021 ; Portugal et al, 2022 ; Wang et al, 2022 ).…”

Roles of microglia in adult hippocampal neurogenesis in depression and their therapeutics

“…Other studies have shown that JAK3 is involved in inhibiting neurogenesis and causing depressive symptoms in animal models under stress ( 128 , 129 ). As a result, JAK3 inhibition has the potential to improve depressive and anxious behavior and restore normal levels of hippocampal neurogenesis in mice subjected to stress ( 130 ). However, microglia modulate the mechanisms of microglia as well as neurogenesis in response to depression via the JAK/STAT signaling pathway is unclear.…”