ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
PGC-1α negatively regulates extrasynaptic NMDAR activity and excitotoxicity.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed.
- Article
- PEG300 Protects Mitochondrial Function By Upregulating PGC-1α to Delay Central Nervous System Oxygen Toxicity in Mice.Neurotoxicity research · 2024Article
- Irisin/PGC-1α/FNDC5 pathway in Parkinson's disease: truth under the throes.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- A comparison of basal and activity-dependent exon splicing in cortical-patterned neurons of human and mouse origin.Frontiers in molecular neuroscience · 2024Article
- Long-term plasticity of astrocytic phenotypes and their control by neurons in health and disease.Essays in biochemistry · 2023Review
- Differential splicing choices made by neurons and astrocytes and their importance when investigating signal-dependent alternative splicing in neural cells.Frontiers in molecular neuroscience · 2023Article
- Targeting NMDA Receptors in Emotional Disorders: Their Role in Neuroprotection.Brain sciences · 2022Review
- NMDA Receptor C-Terminal Domain Signalling in Development, Maturity, and Disease.International journal of molecular sciences · 2022Review
- Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease.Pharmacological reviews · 2022Review
- Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology.Nature communications · 2022Article
- Mitochondrial Abnormalities and Synaptic Damage in Huntington's Disease: a Focus on Defective Mitophagy and Mitochondria-Targeted Therapeutics.Molecular neurobiology · 2021Review
- Microglial identity and inflammatory responses are controlled by the combined effects of neurons and astrocytes.Cell reports · 2021Article
- Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis.Brain sciences · 2021Article
- Targeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation.Cell death & disease · 2021Article
- Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis.Acta neuropathologica · 2021Article
- The Regulation of Astrocytic Glutamate Transporters in Health and Neurodegenerative Diseases.International journal of molecular sciences · 2020Review
- The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer's Disease and Other Neurodegenerative Disorders.Neurochemical research · 2020Review
- Neuronal Activity and Its Role in Controlling Antioxidant Genes.International journal of molecular sciences · 2020Review
- The beneficial effects of physical exercise in the brain and related pathophysiological mechanisms in neurodegenerative diseases.Laboratory investigation; a journal of technical methods and pathology · 2019Review
- Irisin protects the substantia nigra dopaminergic neurons in the rat model of Parkinson's disease.Iranian journal of basic medical sciences · 2019Article
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7 authors.
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Abstract
Underexpression of the transcriptional coactivator PGC-1α is causally linked to certain neurodegenerative disorders, including Huntington's Disease (HD). HD pathoprogression is also associated with aberrant NMDAR activity, in particular an imbalance between synaptic versus extrasynaptic (NMDAR(EX)) activity. Here we show that PGC-1α controls NMDAR(EX) activity in neurons and that its suppression contributes to mutant Huntingtin (mHtt)-induced increases in NMDAR(EX) activity and vulnerability to excitotoxic insults. We found that knock-down of endogenous PGC-1α increased NMDAR(EX) activity and vulnerability to excitotoxic insults in rat cortical neurons. In contrast, exogenous expression of PGC-1α resulted in a neuroprotective reduction of NMDAR(EX) currents without affecting synaptic NMDAR activity. Since HD models are associated with mHtt-mediated suppression of PGC-1α expression, as well as increased NMDAR(EX) activity, we investigated whether these two events were linked. Expression of mHtt (148Q) resulted in a selective increase in NMDAR(EX) activity, compared with wild-type Htt (18Q), and increased vulnerability to NMDA excitotoxicity. Importantly, we observed that the effects of mHtt and PGC-1α knockdown on NMDAR(EX) activity and vulnerability to excitotoxicity were nonadditive and occluded each other, consistent with a common mechanism. Moreover, exogenous expression of PGC-1α reversed mtHtt-mediated increases in NMDAR(EX) activity and protected neurons against excitotoxic cell death. The link between mHtt, PGC-1α, and NMDAR activity was also confirmed in rat striatal neurons. Thus, targeting levels of PGC-1α expression may help reduce aberrant NMDAR(EX) activity in disorders where PGC-1α is underexpressed.
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