Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

Abstract

In patients with major depressive disorder or bipolar disorder, abnormalities in excitatory and/or inhibitory neurotransmission and neuronal plasticity may lead to aberrant functional connectivity patterns within large brain networks. Network dysfunction in association with altered brain levels of glutamate and gamma-aminobutyric acid have been identified in both animal and human studies of depression. In addition, evidence of an antidepressant response to subanesthetic-dose ketamine has led to a collection of studies that have examined neurochemical (e.g., glutamatergic and gamma-aminobutyric acidergic) and functional imaging correlates associated with such an effect. Results from these studies suggest that an antidepressant response in association with ketamine occurs, in part, by reversing these neurochemical/physiological disturbances. Future studies in depression will require a combination of neuroimaging approaches from which more biologically homogeneous subgroups can be identified, particularly with respect to treatment response biomarkers of glutamatergic modulation.

Keywords: Bipolar disorder; Glutamate; Ketamine; Major depressive disorder; Mood disorder; NMDA receptor antagonist.

Published by Elsevier Inc.

Figures

Figure 1. The Cellular and Molecular Effects of Ketamine on Glutamatergic and GABAergic Metabolism and Neurotransmission

(A) Normal glutamatergic and GABAergic metabolism and neurotransmission: Glutamate (Glu) is packaged into vesicles via vesicular glutamate transporters (vGluTs) for exocytotic release. After neuronal depolarization and release into the synaptic cleft, Glu binds to NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, or metabotropic receptors (mGluRs). Glu is removed from the synapse by Glu transporters in astrocytes and metabolically converted into glutamine (Gln) via glutamine synthetase. Gln is released by astrocytes into presynaptic neurons where it is converted back to Glu via cytosolic glutaminase. Inhibitory GABAergic neurons contain the enzyme glutamic acid decarboxylase (GAD), which converts Glu to GABA. (B) Ketamine-induced changes, depicted in red: Ketamine antagonizes N-methyl-D-aspartate (NMDA) receptors on GABAergic interneurons and on post-synaptic neurons; the former disinhibits cortical glutamatergic neurons and the latter increases synthesis of brain-derived neurotrophic factor (BDNF). Via the kainate receptor, ketamine increases activity of mammalian target of rapamycin (mTOR) leading to neuroplasticity and synaptogenesis. Ketamine also increases BDNF via nitric oxide production, leading to stabilization of Nitrergic Rheb and enhancement of mTOR signaling.

Figure 2. Proposed Regions of Interest to Identify Alterations in Glu/GABA and Abnormalities in Functional Connectivity

Sagittal, axial, and coronal viewpoints showing the medial prefrontal cortex (mPFC) in yellow. Sagittal viewpoint showing the fronto-parietal cortical region in red and the dorsal anterior cingulate cortex (dACC) in blue. Sagittal and coronal viewpoints showing the subgenual anterior cingulate cortex (sgACC) in green. Axial viewpoint showing the dorsolateral prefrontal cortex (DLPFC) in purple. Hippocampus and amygdala not shown in figure. *Modified with permission: http://onlinelibrary.wiley.com/doi/10.1002/jmri.24970/full#jmri24970-fig-0001