Is there a role for glutamate-mediated excitotoxicity in inflammation-induced depression?

Abstract

Chronic inflammation in physically ill patients is often associated with the development of symptoms of depression. The mechanisms that are responsible for inflammation-associated depression have been elucidated over the last few years. Kynurenine produced from tryptophan in a reaction catabolized by indoleamine 2,3 dioxygenase is transported into the brain where it is metabolized by microglial enzymes into a number of neurotropic compounds including quinolinic acid, an agonist of N-methyl-D-aspartate receptors. Quinolinic acid can synergize with glutamate released by activated microglia. This chain of events opens the possibility to treat inflammation-induced depression using therapies that target the transport of kynurenine through the blood-brain barrier, the production of quinolinic acid and glutamate by activated microglia, or the efflux of glutamate from the brain to the blood.

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Nevertheless, there are several important non-vesicular (non-exocytotic) mechanisms responsible for glutamate release in pathological contexts (Malarkey and Parpura, 2008;Zhou and Danbolt, 2014) including: (1) release through anion channels (Wang et al, 2013a); (2) reverse efflux through EAATs (Ye and Sontheimer, 1996), (3) release by xC transporters as part of the cystine-glutamate exchange process (Lewerenz et al, 2013), (4) astrocytic vesicular glutamate release during gliotransmission (Petrelli and Bezzi, 2016) and release through hemi-channels on astrocytes and microglia (Malarkey and Parpura, 2008). A detailed review of the functioning of these release mechanisms is beyond the scope of this review, and the reader is directed elsewhere (Dantzer and Walker, 2014;Malarkey and Parpura, 2008;Najjar et al, 2013;Tilleux and Hermans, 2007). A brief overview is presented below.…”

“…Several excellent reviews on this topic are available for further reference (Malarkey and Parpura, 2008;Ohgoh et al, 2002;Tavares et al, 2002;Tilleux and Hermans, 2007;Vercellino et al, 2007). Although glutamate removal from the extracellular space by EAATs is sufficient to prevent excitotoxicity from physiological levels of glutamate release (Bergles and Jahr, 1997;Rothstein, 1996), it is often inadequate in pathological contexts such as during immune activation (Danbolt, 2001;Dantzer and Walker, 2014;Zhou and Danbolt, 2014).…”

“…Brain extracellular levels of glutamate are normally maintained in the micromolar range by EAATs but can rapidly increase 100-fold during microglial and macrophage release (Dantzer and Walker, 2014;Leibowitz et al, 2012). However, when glutamate concentrations become excessive through contributions from activated microglia and macrophages, the EAAT uptake mechanism may be insufficient to clear the entire glutamate load with further impairment of glutamate clearance (Gras et al, 2012;Takaki et al, 2012).…”

“…This strategy has met with some success in reducing glutamate-induced excitotoxicity following experimental induction of stroke (Leibowitz et al, 2012). More recently, this strategy of glutamate 'scavenging' has been proposed as a possible means to reduce excessive glutamate activity as a result of increased inflammation (Dantzer and Walker, 2014).…”

“…During inflammatory conditions, tryptophan is shunted away from serotonin synthesis into the KYN pathway, which is an alternative catabolic pathway for tryptophan resulting in the generation of multiple glutamate-like metabolites that can trigger neurotoxicity and oxidative stress (Dantzer and Walker, 2014;Schwarcz, 2016). The metabolism of tryptophan through the KYN pathway is initiated by activation of tryptophancatabolizing enzymes IDO-1 and 2, and tryptophan-2,3-dioxygenase (TDO) (Schwarcz, 2004(Schwarcz, , 2016Schwarcz et al, 2012;Schwarcz and Pellicciari, 2002).…”