The Huck Institutes of the Life Sciences

Researchers propose new cause of major depressive disorder

GABAergic deficits appear to play a central and causal role in Major Depressive Disorder, a neuropsychiatric disorder affecting approximately 17% of the population worldwide, according to researchers from the Center for Molecular Investigation of Neurological Disorders.

Drawing on a wide body of research including both older and emerging evidence, the researchers propose that mood disorders result from both genetic and stress-induced deficits in GABAergic transmission and that the current therapeutic approaches are effective as a result of downstream alterations of GABA transmission.

Comparatively modest deficits in GABAergic transmission are sufficient to cause most of the cellular, behavioral, cognitive and pharmacological sequelae expected of an animal model of major depression. Additionally, the impact of estrus and pregnancy associated changes in steroid hormone synthesis on GABAergic transmission could explain the increased prevalence of major depression among women, they point out. However, despite a large body of evidence supporting the role of GABAergic transmission in major depression, a number of questions remain: current GABA-potentiating drugs are ineffective anti-depressants – would next-generation GABAergic drugs that are more selective for GABA-A receptors expressed in corticolimbic circuits affected in depression be more effective? A number of aspects of MDDs are not known to involve GABAergic deficits – is there a connection? What role is played by inflammation and apoptosis and oligodendrocyte dysfunction, which have been recently implicated in depression, but are not currently known to be linked to GABAergic deficits?

The team, which included Bernhard Luscher, Qiuying Shen and Nadia Sahir, proposes that future research addresses these questions in order to find improved antidepressant therapies that correct the causal neurochemical imbalances rather than just the symptoms of depression.

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