Wnt signaling in neuropsychiatric disorders: Ties with adult hippocampal neurogenesis and behavior

Abstract

In an effort to better understand and treat mental disorders, the Wnt pathway and adult hippocampal neurogenesis have received increased attention in recent years. One is a signaling pathway regulating key aspects of embryonic patterning, cell specification, and adult tissue homeostasis. The other is the generation of newborn neurons in adulthood that integrate into the neural circuit and function in learning and memory, and mood behavior. In this review, we discuss the growing relationship between Wnt signaling-mediated regulation of adult hippocampal neurogenesis as it applies to neuropsychiatric disorders. Evidence suggests dysfunctional Wnt signaling may aberrantly regulate new neuron development and cognitive function. Indeed, altered expression of key Wnt pathway components are observed in the hippocampus of patients suffering from neuropsychiatric disorders. Clinically-utilized mood stabilizers also proceed through modulation of Wnt signaling in the hippocampus, while Wnt pathway antagonists can regulate the antidepressant response. Here, we review the role of Wnt signaling in disease etiology and pathogenesis, regulation of adult neurogenesis and behavior, and the therapeutic targeting of disease symptoms.

Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications

“…A tight link between hippocampal plasticity, depression, and memory has been suggested [141], and antidepressants were found to modulate hippocampal LTP [142,143]. Wnt signaling components are expressed in the adult dentate gyrus, and the regulation of Wnt expression is accompanied with evidence of change in neurogenesis, suggesting that Wnt signaling is a principal regulator of adult hippocampal neurogenesis [136]. Microarray analysis demonstrated that citalopram, fluoxetine, venlafaxine, and atomoxetine modulate rat hippocampal gene expression of Wnt pathway components [144].…”

“…Recent studies have largely focused on identifying cellular and molecular mechanisms underlying hippocampal plasticity in response to stress and antidepressant treatments. Changes in neurotrophin level and activity (e.g., activin pathway [134], BDNF, and CREB1 [135]), intracellular signaling pathways (e.g., Wnt signaling [136] and mTOR signaling [137]), direct modulators of synaptic plasticity (e.g., GAP43 [138]), and/or synaptic function/structure (SNAP25, DLG2, MAP1A) and glutamate receptor subunits (GLUR1 and GLUR3) [139] have been implicated. Pathway analyses in depressive subjects have been scarcely performed, and these data mainly derived from analyses on single molecules pertaining to a pathway and/or animal models.…”

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

“…While this is the case in mature, differentiated cells under basal conditions, the activity of GSK3 is much lower in stem/precursor cells due to the action of growth factors and Wnt molecules. Therefore, in BD over activity of GSK3 may undermine neurogenesis, and psychotropic agents by enhancing this process promote mood stabilization 27). Further, detailed characterization of this mode of action of mood stabilizing medications can result in targeted therapeutics of BD.…”

Environmental Enrichment Improves Spatial Learning and Memory in Vascular Dementia Rats with Activation of Wnt/β-Catenin Signal Pathway

“…The wnt/β-catenin signal pathway has emerged as a crucial pathway in neuronal self-renewal, proliferation, differentiation, maturation, and functional integration [10]. It has been proved to facilitate long-term potentiation [11] and deregulation of the wnt/β-catenin pathway has been implicated in the pathology of AD [12].…”