title: Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders.
abstract: Both bipolar disorder (BD) and major depressive disorder (MDD) have high morbidity and share a genetic background. Treatment options for these mood disorders are currently suboptimal for many patients; however, specific genetic variables may be involved in both pathophysiology and response to treatment. Agents such as the glutamatergic modulator ketamine are effective in treatment-resistant mood disorders, underscoring the potential importance of the glutamatergic system as a target for improved therapeutics. Here we review genetic studies linking the glutamatergic system to the pathophysiology and therapeutics of mood disorders. We screened 763 original genetic studies of BD or MDD that investigated genes encoding targets of the pathway/mediators related to the so-called tripartite glutamate synapse, including pre- and post-synaptic neurons and glial cells; 60 papers were included in this review. The findings suggest the involvement of glutamate-related genes in risk for mood disorders, treatment response, and phenotypic characteristics, although there was no consistent evidence for a specific gene. Target genes of high interest included GRIA3 and GRIK2 (which likely play a role in emergent suicidal ideation after antidepressant treatment), GRIK4 (which may influence treatment response), and GRM7 (which potentially affects risk for mood disorders). There was stronger evidence that glutamate-related genes influence risk for BD compared with MDD. Taken together, the studies show a preliminary relationship between glutamate-related genes and risk for mood disorders, suicide, and treatment response, particularly with regard to targets on metabotropic and ionotropic receptors.
authors: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, NIH, Bethesda, MD, USA.|Laboratory of Neuroscience, LIM- 27, Institute and Department of Psychiatry, University of São Paulo, São Paulo, Brazil.
authors: Rafael T
authors: RT
authors: de Sousa
authors: Laboratory of Neuroscience, LIM- 27, Institute and Department of Psychiatry, University of São Paulo, São Paulo, Brazil.
authors: Alexandre A
authors: http://orcid.org/0000-0002-0006-8107
authors: AA
authors: Loch
authors: Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.
authors: André F
authors: AF
authors: Carvalho
authors: Laboratory of Neuroscience, LIM- 27, Institute and Department of Psychiatry, University of São Paulo, São Paulo, Brazil.
authors: André R
authors: AR
authors: Brunoni
authors: Section on Translational Neuroscience, National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
authors: Marie Reine
authors: MR
authors: Haddad
authors: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, NIH, Bethesda, MD, USA.
authors: Ioline D
authors: ID
authors: Henter
authors: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, NIH, Bethesda, MD, USA.
authors: Carlos A
authors: CA
authors: Zarate
authors: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, NIH, Bethesda, MD, USA.|Laboratory of Neuroscience, LIM- 27, Institute and Department of Psychiatry, University of São Paulo, São Paulo, Brazil.|Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil.
authors: Rodrigo
authors: R
authors: Machado-Vieira
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D003865:Major Depressive Disorder / Q000235:genetics*; D006801:Humans; D017470:Receptors, Glutamate / Q000235:genetics*
chemical_list: D017470:Receptors, Glutamate