Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice

Abstract

IntroductionDepression is the most common psychiatric illness, with about 121 million people affected worldwide. Of people who experience a depressive episode, 15% commit suicide.1,2 Although many studies have investigated the pathophysiologic mechanisms of major depressive disorder (MDD) using live brain imaging and postmortem studies, its etiology remains unclear; however, recent progress based on those studies has gradually revealed common features of MDD. Among these features, volume reduction of selective brain regions in patients with MDD is the most remarkable.3-5 This is mainly due to a lower number of glial cells and neuronal atrophy in those regions. 6,7 Specifically, the reduction of astrocytes among all glial cells was frequently found in postmortem studies. 3,[8][9][10] Another study reported lower levels of glutamine synthetase (GS), one of the astrocyte-specific enzymes involved in the glutamate-glutamine (Glu-Gln) cycle, and its activity levels were decreased in some clinical studies of MDD. 11A variety of preclinical studies have reported findings to support the idea of astrocyte loss and Glu-Gln disruption. Consistent with those studies, several papers have reported decreased gliogenesis and number of astrocytes in the medial prefrontal cortex (mPFC) in animal models of chronic stressinduced depression.7,12-14 These results strongly suggest that a relationship exists between the functions of astrocytes and the behavioural aspects of MDD. To test this issue, a recent study ablated astrocytes in the prelimbic cortex (PLC) using a specific toxin and revealed that depressive-like behaviours could be evoked using only this treatment.14 It remains to be determined how astrocyte loss results in depressive behaviours.To address this question, we focused on the role of astrocytes Background: The brain levels of glutamate (Glu) and glutamine (Gln) are partially regulated through the Glu-Gln cycle. Astrocytes play a role in regulating the Glu-Gln cycle, and loss of astrocytes has been associated with depressive disorders. We hypothesized that levels of Glu and Gln would be affected by astrocyte loss and dysregulation of the Glu-Gln cycle and that depressive-like behaviours would be closely related to the level of changes in Glu and Gln. Methods: We used liquid chromatography to measure Glu and Gln concentrations in the prefrontal cortex of male mice infused with L-α aminoadipic acid (L-AAA), a specific astrocyte toxin, in the prelimbic cortex. Methionine sulfoximine, a Gln synthetase inhibitor, and α-methyl-amino-isobutyric acid, a blocker of neuronal Gln transporters, were used to disturb the Glu-Gln cycle. We assessed the behavioural change by drug infusion using the forced swim test (FST) and sucrose preference test. Results: The Glu and Gln levels were decreased on the fifth day after L-AAA infusion, and the infused mice showed longer durations of immobility in the FST and lower sucrose preference, indicative of depressive-like behaviour. Mice in which Gln synthetase or Gln transport were inhibited al...

Astrocyte Pathology in Major Depressive Disorder: Insights from Human Postmortem Brain Tissue

“…Furthermore, chronic mild stress significantly decreased levels of GFAP mRNA in rat medial prefrontal cortex [58]. Interestingly, infusion of L-α aminoadipic acid in rodent prefrontal cortex, thought to selectively lesion glial cells including GFAP-IR astrocytes but not neurons, induced depressive-like behaviors [59, 60]. These two lesion studies appear to support the hypothesis that the loss of glia contributes to the pathology of depression [7], although this conclusion rests on the specificity of the toxin to glia.…”

Astrocyte pathology in the prefrontal cortex impairs the cognitive function of rats

“…[45][46][47][48] Furthermore, the medial prefrontal cortex (mPFC) is anatomically and functionally linked with other components of the limbic system, which justifies the key role in cognitive, mnesic and emotional processing. 49,50 Accordingly, astrocyte loss in the PFC is sufficient to induce depression-like behavior in the rat [51][52][53] and blockade of astrocytic glutamate uptake in this region is also sufficient to produce anhedonia, a hallmark of depression. 54 Although these observations may also justify the cognitive dysfunction observed in patients suffering mood disorders the impact of astrocyte loss in the mPFC, and consecutively on mPFCdependent cognitive function is still poorly understood.…”

Validation of chronic restraint stress model in rats for the study of depression using longitudinal multimodal MR imaging

“…Similarly, other 1 H-MRS studies of animal models of depression such as the chronic mild stress and the chronic social isolation models have reported decreases in these neurometabolites in the prefrontal cortex (Hemanth Kumar et al, 2012) and hippocampus (Hemanth Kumar et al, 2012;Shao et al, 2015). The correlation between decreasing Glu and Glx levels and reduced climbing behaviour during FST suggests that the shortage in these neurometabolites might be due to a reduction in the number of astrocytes which in turn alters neuronal activity and therefore may contribute to depression-like behaviours, as previously shown in an L-α aminoadipic acid (L-AAA) infusion mouse model (Lee et al, 2013).…”