ReviewTowards a glutamate hypothesis of depression: An emerging frontier of neuropsychopharmacology for mood disorders
Highlights
► Pathophysiology of depression is associated with dysfunction of glutamatergic system. ► Drugs targeting glutamate system may have rapid and sustained antidepressant effects. ► A paradigm shift from monoamine to glutamate may bring new impulse to the field.
Section snippets
Introduction. Do we need a glutamate hypothesis of depression?
The fields of neuropsychopharmacology and biological psychiatry have been dominated for over half a century by the monoamine hypothesis, which has driven the research on pathophysiology of neuropsychiatric disorders, in particular mood/anxiety disorders, as well as the development of therapeutic drugs. The basic version of the hypothesis, with regard to depression, speculated that pathology was due to (or accompanied by) reduced availability of monoamines, particularly serotonin and
Brain is in good part a glutamatergic/GABAergic machine
Although it was not readily recognized as a neurotransmitter until the early 1980s, much later than the monoaminergic transmitters, the amino acid glutamate is now accepted as the major excitatory neurotransmitter in the nervous system (Orrego and Villanueva, 1993). Glutamate mediates the vast majority of fast excitatory transmission in the brain, while γ-aminobutyric acid (GABA), another amino acid neurotransmitter, mediates the vast majority of fast inhibitory transmission. As an example, it
Emotion vs cognition. The role of glutamate transmission
The last three decades of neurobiological research have clearly associated cognitive processes in the brain with functional and structural changes in glutamate neurotransmission. A wealth of studies (particularly in the hippocampus) have shown that activity-dependent changes in the synaptic strength of central glutamate synapses correlate with the processes of learning and memory, and that interfering with these changes impairs the fixation of memories (Citri and Malenka, 2008, Diamond et al.,
Glutamate levels: plasma, cerebrospinal fluid, tissue studies
There is now rapidly growing evidence that pathophysiological changes within the amino acid neurotransmitter systems are associated with mood and cognitive dysfunction. Similar to reports of wide ranging abnormalities in GABA content in individuals with mood disorders (Brambilla et al., 2003, Tunnicliff and Malatynska, 2003, Sanacora and Saricicek, 2007), glutamatergic abnormalities have been demonstrated in the plasma, cerebrospinal fluid (CSF) and brain tissue of individuals afflicted with
Cytoarchitectural and morphological correlates to mood disorders
Consistent with the idea that changes in glial cell function may be related to the reports of abnormal levels of glutamate and glutamine in patients with mood disorders, reduced numbers and density of glial cells have been reported in a number of postmortem studies (Rajkowska, 2000, Rajkowska et al., 1999, Rajkowska et al., 2001, Bowley et al., 2002, Miguel-Hidalgo et al., 2002, Webster et al., 2001, Cotter et al., 2001, Miguel-Hidalgo et al., 2000, Ongur et al., 1998, Hamidi et al., 2004) (see
Dendritic remodeling in the brain. Evidence from preclinical stress models
The effects of stress on structural remodeling in the brain have been investigated by a number of studies (for a review see: Gorman and Docherty, 2010, Holmes and Wellman, 2009, McEwen, 2005, Musazzi et al., 2011, Pittenger and Duman, 2008, Shansky and Morrison, 2009). The largest number of studies has been carried out in hippocampus, but prefrontal cortex and amygdala were also analyzed (Table 1). Different forms of stress have been shown to induce atrophy, retraction and consistently
The effects of stress and glucocorticoids on glutamate synapses and neurotransmission
A remarkable feature of glutamate synapses is their ability to undergo structural, as well as functional change, in response to environmental stimuli (Südhof and Malenka, 2008, Wong and Ghosh, 2002). Accordingly, synaptic terminals, spines and dendritic branches are constantly remodeled as a result of experience, learning and memory, emotion processing. As outlined above, environmental stress has a heavy impact on brain tissue morphology and is considered a risk factor for mood/anxiety
Antidepressant agents and glutamate: preclinical evidence
The monoamine hypothesis was largely based on the serendipitous discovery of the first antidepressant agents. However, early findings that these drugs affect synaptic plasticity, modulate the function of NMDA-R, and that NMDA-R antagonists possess antidepressant activity, have started a variegated field of research that in time has contributed to disclose the role of glutamatergic system in mood disorder and in antidepressant action. In this section, we summarize the known effects of
Conclusions: future perspectives and novel targets
There is compelling accumulated evidence that long-term changes in an array of brain areas and circuits mediating complex cognitive–emotional behaviors represent the biological underpinnings of mood/anxiety disorders. As the vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, today it would be limiting to maintain that glutamate is in some way ‘involved’ in these neuropsychiatric disorders; rather it should be recognized that the glutamatergic
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