Transcriptomic responses in mouse brain exposed to chronic excess of the neurotransmitter glutamate

Wang, Xinkun; Bao, Xiaodong; Pal, Ranu; Agbaş, Abdulbakî; Michaelis, Elias K.

doi:10.1186/1471-2164-11-360

Cited by 34 publications

(41 citation statements)

References 101 publications

(117 reference statements)

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“…To test our hypothesis that chronic asymptomatic domoic acid exposure in zebrafish produces brain transcriptome-level changes consistent with chronic excess synaptic glutamate release, we compared the gene transcriptome changes in zebrafish with reported gene transcriptome changes in the hippocampi of Glud1 transgenic mice (Wang et al, 2010). This mouse model was developed in order to study the neurological consequences of excess glutamatergic stimulation, and constitutively over-expresses a copy of the glud1 gene, leading to moderate over-production of glutamate and increased (~30%) release of glutamate during synaptic transmission (Bao et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

“…We compared transcriptome results from the brains of chronically-exposed zebrafish to hippocampi from nine-month old Glud1 mice (Wang et al, 2010), and identified transcriptional changes for genes from two IPA Bio Functions groups in both the present study and the Glud1 mouse study: 1) Nervous System Function & Development ; and 2) Cell Death . However, individual gene transcription responses in zebrafish were different from those reported in the Glud1 mouse hippocampus (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We hypothesized that: 1) chronic asymptomatic domoic acid exposure would lead to a consistent gene transcription profile in the brains of exposed zebrafish; and 2) this profile would be similar to the gene transcription profile in the hippocampi of Glud1 transgenic mice, a model of chronic moderate glutamatergic over-stimulation (Bao et al, 2009; Wang et al, 2010). We found that genes and biological functions related to neurological function and development were significantly altered; however, the transcriptome response was highly-variable across exposure duration, with little to no overlap of specific genes across the six exposure duration time points.…”

Section: Discussionmentioning

confidence: 99%

“…We anticipated that the whole-brain transcriptome profile in zebrafish chronically-exposed to asymptomatic domoic acid doses would be similar to the hippocampal transcriptome response in the Glud1 transgenic mouse model (Wang et al, 2010). This transgenic line transcribes extra copies of Glud1 (glutamate dehydrogenase 1) under the control of the promoter for neuron-specific enolase ( Nse ) in neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Potential health risks of chronically elevated glutamatergic activity, like those that might result from chronic/episodic DA exposure, are also supported by the studies of a transgenic mouse model selectively overexpressing neuronal glutamate dehydrogenase ( Glud1 ). Bao et al (2009) and Wang et al (2010) demonstrated that chronic moderately-elevated synaptic glutamate in the Glud1 mice leads to reductions in glutamate synapses in specific (vulnerable) brain regions, with reductions in glutamate synapses increasing with advancing age (Bao et al, 2009). Notably, these decreases in glutamate synapses were associated with upregulation of cellular pathways associated with nervous system development, neuronal growth, and synaptic transmission, as well as oxidative stress, cell injury, and inflammation, indicating apparent compensatory responses to stress that promoted growth of neuronal processes (Wang et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS

Hiolski¹,

Kendrick²,

Frame³

et al. 2014

Aquatic Toxicology

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Domoic acid is an algal-derived seafood toxin that functions as a glutamate agonist and exerts excitotoxicity via overstimulation of glutamate receptors (AMPA, NMDA) in the central nervous system (CNS). At high (symptomatic) doses, domoic acid is well-known to cause seizures, brain lesions and memory loss; however, a significant knowledge gap exists regarding the health impacts of repeated low-level (asymptomatic) exposure. Here, we investigated the impacts of low-level repetitive domoic acid exposure on gene transcription and mitochondrial function in the vertebrate CNS using a zebrafish model in order to: 1) identify transcriptional biomarkers of exposure; and 2) examine potential pathophysiology that may occur in the absence of overt excitotoxic symptoms. We found that transcription of genes related to neurological function and development were significantly altered, and that asymptomatic exposure impaired mitochondrial function. Interestingly, the transcriptome response was highly-variable across the exposure duration (36 weeks), with little to no overlap of specific genes across the six exposure time points (2, 6, 12, 18, 24, and 36 weeks). Moreover, there were no apparent similarities at any time point with the gene transcriptome profile exhibited by the glud1 mouse model of chronic moderate excess glutamate release. These results suggest that although the fundamental mechanisms of toxicity may be similar, gene transcriptome responses to domoic acid exposure do not extrapolate well between different exposure durations. However, the observed impairment of mitochondrial function based on respiration rates and mitochondrial protein content suggests that repetitive low-level exposure does have fundamental cellular level impacts that could contribute to chronic health consequences.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS

Hiolski¹,

Kendrick²,

Frame³

et al. 2014

Aquatic Toxicology

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Synaptic underpinnings of altered hippocampal function in glutaminase‐deficient mice during maturation

et al. 2012

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Glutaminase-deficient mice (GLS1 hets), with reduced glutamate recycling, have a focal reduction in hippocampal activity, mainly in CA1, and manifest behavioral and neurochemical phenotypes suggestive of schizophrenia resilience. To address the basis for the hippocampal hypoactivity, we examined synaptic plastic mechanisms and glutamate receptor expression. While baseline synaptic strength was unaffected in Schaffer collateral inputs to CA1, we found that long-term potentiation was attenuated. In wild-type mice, GLS1 gene expression was highest in the hippocampus and cortex, where it was reduced by about 50% in GLS1 hets. In other brain regions with lower wild-type GLS1 gene expression there were no genotypic reductions. In adult GLS1 hets, NMDA receptor NR1 subunit gene expression was reduced, but not AMPA receptor GluR1 subunit gene expression. In contrast, juvenile GLS1 hets showed no reductions in NR1 gene expression. In concert with this, adult GLS1 hets showed a deficit in hippocampal-dependent contextual fear conditioning while juvenile GLS1 hets did not. These alterations in glutamatergic synaptic function may partly explain the hippocampal hypoactivity seen in the GLS1 hets. The maturity-onset reduction in NR1 gene expression and in contextual learning supports the premise that glutaminase inhibition in adulthood should prove therapeutic in schizophrenia.

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Deregulation of glutamate dehydrogenase in human neurologic disorders

Plaitakis

Zaganas

Spanaki

2013

J of Neuroscience Research

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Mammalian glutamate dehydrogenase is an allosterically regulated enzyme that is central to glutamate metabolism. It contributes to important cellular processes, including Krebs cycle anaplerotic mechanisms, energy production, and ammonia homeostasis. In addition to this housekeeping hGDH1, humans have acquired through duplication an hGDH2 isoenzyme expressed in neural tissues with distinct regulatory properties. There is increasing evidence that deregulation of human GDHs leads to human disorders. Thus, in hGDH1, regulatory mutations that attenuate GTP inhibition can result in the hyperinsulinism/hyperammonemia syndrome, which is often associated with epileptic seizures, mental retardation, and generalized dystonia. Also, transgenic overexpression of GLUD1 in neurons has resulted in age-dependent degeneration of the CA1 behippocampal region, associated with upregulation of α-synuclein and other proteins linked to major human movement disorders. With regard to hGDH2, a rare T1492G variation in the GLUD2 gene, resulting in substitution of Ala for Ser445 in the regulatory domain of hGDH2, interacts significantly with Parkinson's disease (PD) onset. In two independent Greek and one North American PD cohorts, Ser445Ala hemizygous males, but not heterozygous females, developed PD 6-13 years earlier than subjects with other genotypes. The Ala445-hGDH2 variant displays increased catalytic activity that is amenable to inhibition by estrogens. Enhanced glutamate oxidation by Ala445-hGDH2 is thought to accelerate nigral cell degeneration in hemizygous males, and inhibition of the overactive variant by estrogens may protect heterozygous females. Hence, deregulation of hGDH1 and hGDH2 may play a role in degenerative processes, so these observations identify novel targets for therapeutic intervention in human disorders.

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Transcriptomic responses in mouse brain exposed to chronic excess of the neurotransmitter glutamate

Cited by 34 publications

References 101 publications

Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS

Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS

Synaptic underpinnings of altered hippocampal function in glutaminase‐deficient mice during maturation

Deregulation of glutamate dehydrogenase in human neurologic disorders

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