Glycogen synthase kinase-3 as a therapeutic target for cognitive dysfunction in neuropsychiatric disorders.

Abstract

The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) is involved in a broad range of cellular processes including cell proliferation, apoptosis and inflammation. It is now also increasingly acknowledged as having a role to play in cognitive-related processes such as neurogenesis, synaptic plasticity and neural cell survival. Cognitive impairment represents a major debilitating feature of many neurodegenerative and psychiatric disorders, including Alzheimer's disease, mood disorders, schizophrenia and fragile X syndrome, as well as being a result of traumatic brain injury or cranial irradiation. Accordingly, GSK-3 has been identified as an important therapeutic target for cognitive impairment, and recent preclinical studies have yielded important evidence demonstrating that GSK-3 inhibitors may be useful therapeutic interventions for restoring cognitive function in some of these brain disorders. The current review summarises the role of GSK-3 as a regulator of cognitive-dependent functions, examines current preclinical and clinical evidence of the potential of GSK-3 inhibitors as therapeutic agents for cognitive impairments in neuropsychiatric disorders, and offers some insight into the current obstacles that are impeding the clinical use of selective GSK-3 inhibitors in the treatment of cognitive impairment.