Dimensions of GSK3 Monoamine-Related Intracellular Signaling in Schizophrenia

Abstract Since the discovery of the mechanism of action of typical antipsychotics in 1975, the dopamine theory of schizophrenia remains one of the principal doctrines to explain the pathogenesis of schizophrenia. According to this theory, increased dopaminergic neurotransmission involving D2 receptors results in dysregulation of intracellular signaling mechanisms, leading to manifestations of schizophrenia. D2 receptors signal through G protein-dependent and G protein-independent pathways, the latter involving Akt/GSK3 has proved to play a major role to the schizopheric phenotypes. GSK3 is known to play central roles in the regulation of metabolism, synaptic plasticity, and neurodevelopment. Moreover, several prominent risk factors and contributors of the disease converge on these downstream effectors of D2 receptor signaling. Finally, the medications used clinically for the management of schizophrenia affect this signaling pathway. Here, we review the signaling systems altered in schizophrenia with a focus on GSK3 networks and discuss their involvement in the pathophysiology of the disease as well as their potential for the development of diagnostic and therapeutic tools.