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.

Keywords: Adult neurogenesis; Hippocampus; Psychiatric disorders; Wnt signaling.

Figure 1

Summary of the role of Wnt signaling in adult hippocampal neurogenesis. (A) A schematic diagram of adult hippocampal neurogenesis is depicted across the subgranular zone (SGZ) and granular cell layer (GCL) of the dentate gyrus. An activated precursor cell passes through distinct phases as it differentiates and integrates with an elaborate morphology into the circuit; (B) The effect of different components of the canonical Wnt signaling pathway are shown across different stages of neurogenesis.

Figure 2

Schematic illustration of canonical Wnt/β-catenin signaling. Left panel shows the downstream Wnt pathway following stimulation by a Wnt ligand and subsequent translocation of β-catenin (β-cat) into the nucleus. Right panel shows the downstream pathway following inhibition by Wnt antagonists and subsequent proteasomal degradation of β-catenin.