Chronic hypothalamic-pituitary-adrenal axis disruption alters glutamate homeostasis and neural responses to stress in male C57Bl6/N mice

Kinlein, Scott A.; Wallace, Naomi K.; Savenkova, Marina I.; Karatsoreos, Ilia N.

doi:10.1016/j.ynstr.2022.100466

Cited by 5 publications

(3 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While homozygous C- Glud1 −/− mice show an increase in excitatory transmission under stress-naïve conditions [ 14 ], transcriptional abnormalities implicating pyramidal neuron dysfunction in heterozygous CNS- Glud1 +/− mice are triggered by stress. In CNS- Glud1 +/− /Stress mice, stress may limit the ability of the mPFC to regulate glutamate homeostasis [ 64 , 65 ], and hinder the competency of the mPFC to implement compensatory mechanisms critical for intact homeostasis at the glutamate tripartite and glutamate-GABA synapses. In particular, the present findings point to changes in pyramidal cells, GABA interneurons and oligodendrocytes.…”

Section: Discussionmentioning

confidence: 99%

Synergistic, long-term effects of glutamate dehydrogenase 1 deficiency and mild stress on cognitive function and mPFC gene and miRNA expression

et al. 2023

View full text Add to dashboard Cite

Glutamate abnormalities in the medial prefrontal cortex (mPFC) are associated with cognitive deficits. We previously showed that homozygous deletion of CNS glutamate dehydrogenase 1 (Glud1), a metabolic enzyme critical for glutamate metabolism, leads to schizophrenia-like behavioral abnormalities and increased mPFC glutamate; mice heterozygous for CNS Glud1 deletion (C-Glud1+/− mice) showed no cognitive or molecular abnormalities. Here, we examined the protracted behavioral and molecular effects of mild injection stress on C-Glud1+/− mice. We found spatial and reversal learning deficits, as well as large-scale mPFC transcriptional changes in pathways associated with glutamate and GABA signaling, in stress-exposed C-Glud1+/− mice, but not in their stress-naïve or C-Glud1+/+ littermates. These effects were observed several weeks following stress exposure, and the expression levels of specific glutamatergic and GABAergic genes differentiated between high and low reversal learning performance. An increase in miR203-5p expression immediately following stress may provide a translational regulatory mechanism to account for the delayed effect of stress exposure on cognitive function. Our findings show that chronic glutamate abnormalities interact with acute stress to induce cognitive deficits, and resonate with gene x environment theories of schizophrenia. Stress-exposed C-Glud1+/− mice may model a schizophrenia high-risk population, which is uniquely sensitive to stress-related ‘trigger’ events.

show abstract

Section: Discussionmentioning

confidence: 99%

Synergistic, long-term effects of glutamate dehydrogenase 1 deficiency and mild stress on cognitive function and mPFC gene and miRNA expression

et al. 2023

View full text Add to dashboard Cite

show abstract

“…The involvement of 5-HT and BDNF/TrkB interaction ( Figure 1DE ) in depression has been previously addressed ( Popova & Naumenko, 2019 ). 5-HT receptor activation with agonists promoted the BDNF expression and TrkB phosphorylation, in vivo and in vitro, therefore, the central 5-HT deficiency would lead to reduced BDNF expression and TrkB activation ( de Foubert et al, 2007 ; Pascual-Brazo et al, 2012 ; Samarajeewa et al, 2014 ). In turn, BDNF dose-dependently reduced 5-HT reuptake through affecting the 5-HTT function, with the higher doses presenting more severe reuptake inhibition, in vitro ( Mössner et al, 2000 ).…”

Section: The Underlying Mechanisms Of Os-induced Depressionmentioning

confidence: 99%

“…For HPA-glutamate interaction ( Figure 1CG ), in vitro studies showed activated GRs interacted with TrkB to facilitate the BDNF-promoted glutamate release via PLC-γ signaling ( Numakawa et al, 2009 ), while glucocorticoids attenuated the BDNF-dependent glutamate receptor upregulation ( Kawashima et al, 2010 ). Moreover, chronic HPA axis disruption with corticosterone altered glutamate signaling-related gene expressions in mice, in a way that corticosterone increased mRNA expression of ionotropic glutamate receptor subunits GluR1 and GluR2 in the mPFC, reduced mRNA expression of the NMDA receptor subunits (NR1, NR2B) and mGluR5 in the hippocampus, and decreased mRNA expression the AMPA receptor subunit GluR1 in the amygdala ( Kinlein et al, 2022 ). In turn, glutamate signaling plays a complex role in affecting the HPA responses, probably through driving acute HPA response via the ionotropic receptors postsynaptically, and inhibiting CRH neurons via group I mGluR presynaptically ( Evanson & Herman, 2015b ).…”

Section: The Underlying Mechanisms Of Os-induced Depressionmentioning

confidence: 99%

How Oxidative Stress Induces Depression?

Lei

Chen

et al. 2023

ASN Neuro

View full text Add to dashboard Cite

Depression increasingly affects a wide range and a large number of people worldwide, both physically and psychologically, which makes it a social problem requiring prompt attention and management. Accumulating clinical and animal studies have provided us with substantial insights of disease pathogenesis, especially central monoamine deficiency, which considerably promotes antidepressant research and clinical treatment. The first-line antidepressants mainly target the monoamine system, whose drawbacks mainly include slow action and treatment resistant. The novel antidepressant esketamine, targeting on central glutamatergic system, rapidly and robustly alleviates depression (including treatment-resistant depression), whose efficiency is shadowed by potential addictive and psychotomimetic side effects. Thus, exploring novel depression pathogenesis is necessary, for seeking more safe and effective therapeutic methods. Emerging evidence has revealed vital involvement of oxidative stress (OS) in depression, which inspires us to pursue antioxidant pathway for depression prevention and treatment. Fully uncovering the underlying mechanisms of OS-induced depression is the first step towards the avenue, thus we summarize and expound possible downstream pathways of OS, including mitochondrial impairment and related ATP deficiency, neuroinflammation, central glutamate excitotoxicity, brain-derived neurotrophic factor/tyrosine receptor kinase B dysfunction and serotonin deficiency, the microbiota-gut-brain axis disturbance and hypothalamic-pituitary-adrenocortical axis dysregulation. We also elaborate on the intricate interactions between the multiple aspects, and molecular mechanisms mediating the interplay. Through reviewing the related research progress in the field, we hope to depict an integral overview of how OS induces depression, in order to provide fresh ideas and novel targets for the final goal of efficient treatment of the disease.

show abstract