Elevated gene expression of glutamate receptors in noradrenergic neurons from the locus coeruleus in major depression

Abstract

Glutamate receptors are promising drug targets for the treatment of urgent suicide ideation and chronic major depressive disorder (MDD) that may lead to suicide completion. Antagonists of glutamatergic NMDA receptors reduce depressive symptoms faster than traditional antidepressants, with beneficial effects occurring within hours. Glutamate is the prominent excitatory input to the noradrenergic locus coeruleus (LC). The LC is activated by stress in part through this glutamatergic input. Evidence has accrued demonstrating that the LC may be overactive in MDD, while treatment with traditional antidepressants reduces LC activity. Pathological alterations of both glutamatergic and noradrenergic systems have been observed in depressive disorders, raising the prospect that disrupted glutamate-norepinephrine interactions may be a central component to depression and suicide pathobiology. This study examined the gene expression levels of glutamate receptors in post-mortem noradrenergic LC neurons from subjects with MDD (most died by suicide) and matched psychiatrically normal controls. Gene expression levels of glutamate receptors or receptor subunits were measured in LC neurons collected by laser capture microdissection. MDD subjects exhibited significantly higher expression levels of the NMDA receptor subunit genes, GRIN2B and GRIN2C, and the metabotropic receptor genes, GRM4 and GRM5, in LC neurons. Gene expression levels of these receptors in pyramidal neurons from prefrontal cortex (BA10) did not reveal abnormalities in MDD. These findings implicate disrupted glutamatergic-noradrenergic interactions at the level of the stress-sensitive LC in MDD and suicide, and provide a theoretical mechanism by which glutamate antagonists may exert rapid antidepressant effects.

Neuronal correlates of depression

“…Anatomically the LC has reciprocal connections with various regions of the brains also known to be associated with depression [201]. Significant increases in gene expression levels for NMDA and mGluR subunits were found in the LC of post-mortem depressed patients [16] supporting the notion that disrupted glutamatergic-noradrenergic interactions in the LC leads to depression. Electrophysiological measures of basal firing rates of LC neurons in the Wistar Kyoto (WKY) rat, a strain that exhibits depressive and anxiety-like behaviours, was shown to be significantly higher compared to the standard Wistar strain of rats [202].…”

Redefining Noradrenergic Neuromodulation of Behavior: Impacts of a Modular Locus Coeruleus Architecture

“…The LC receives multiple glutamatergic afferents (from paragigantocellularis nucleus, lateral habenula, and PFC) (Herkenham and Nauta, 1979;Arnsten and Goldman-Rakic, 1984;Aston-Jones et al, 1986;Holloway et al, 2013). Activation of these afferents is associated with the onset of salient or goal-relevant stimuli Bouret and Sara, 2004), as well as affective disorders, opiate withdrawal, and neuropathic pain (Aghajanian et al, 1994;Hayashida et al, 2010;Bernard et al, 2011;Chandley et al, 2014;Kimura et al, 2015). Elevated expression of NMDA ionotropic and metabotropic glutamate receptors in the LC have been observed in postmortem tissue from suicide victims, suggesting that such input-output-specific LC modules, activated by particular neurochemicals, may play a role in major depressive disorder (Bernard et al, 2011;Chandley et al, 2014).…”

“…Activation of these afferents is associated with the onset of salient or goal-relevant stimuli Bouret and Sara, 2004), as well as affective disorders, opiate withdrawal, and neuropathic pain (Aghajanian et al, 1994;Hayashida et al, 2010;Bernard et al, 2011;Chandley et al, 2014;Kimura et al, 2015). Elevated expression of NMDA ionotropic and metabotropic glutamate receptors in the LC have been observed in postmortem tissue from suicide victims, suggesting that such input-output-specific LC modules, activated by particular neurochemicals, may play a role in major depressive disorder (Bernard et al, 2011;Chandley et al, 2014). Similarly, recent evidence suggests that increased availability of metabotropic glutamate receptor 5 (mGluR5) is associated with suicide ideation in patients with post-traumatic stress disorder (Davis et al, 2019).…”

Genome-wide association study of depression phenotypes in UK Biobank (n = 322,580) identifies the enrichment of variants in excitatory synaptic pathways

“…GRM5 is expressed in the brain and facilitates glutamatergic neurotransmission. GRM5 has previously been associated with a range of behavioural and neurological phenotypes such as depression 27 , OCD 28 , epilepsy 29 , smoking 30 , Alzheimer's disease 31,32 , autism 33 and schizophrenia 34 . A recent study found a role for Metabotropic glutamate receptor 5 (mGluR5) in relation to stress-induced depression in mice 35 and GRM5…”