ArticleHuman molecular genetics2018
Loss of cerebellar glutamate transporters EAAT4 and GLAST differentially affects the spontaneous firing pattern and survival of Purkinje cells.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 38 citations in OpenAlex.
- Enhanced mGluR1 function causes motor deficits and region-specific Purkinje cell dysfunction.Brain : a journal of neurology · 2026Article
- Impaired motor activity in a CRISPR SCA5 L253P knock-in mouse is associated with selective β-III-spectrin subcellular redistribution in the cerebellum.bioRxiv : the preprint server for biology · 2026Article
- Modulation of glutamate metabolism in Niemann-pick disease type C1 mice.Molecular genetics and metabolism reports · 2026Article
- Amyloid precursor protein modulates cerebellar Purkinje cell activity and motor function through regulation of Nav1.6 currents.PLoS biology · 2025Article
- Automated gait analysis indicates efficacy of T-type calcium channel inhibition for mitigation of disrupted calcium signalling in an SCA5 mouse model.Scientific reports · 2025Article
- Alterations in the NaCerebellum (London, England) · 2025Article
- Phenotypical, genotypical and pathological characterization of the moonwalker mouse, a model of ataxia.Neurobiology of disease · 2024Article
- Synthesis and Structure-Activity Relationships for Glutamate Transporter Allosteric Modulators.Journal of medicinal chemistry · 2024Article
- Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1.Neuron · 2024Article
- Article
- Glutamatergic systems in neuropathic pain and emerging non-opioid therapies.Pharmacological research · 2022Review
- Article
- Molecular Basis of Coupled Transport and Anion Conduction in Excitatory Amino Acid Transporters.Neurochemical research · 2022Review
- Reduction of glutamate neurotoxicity: A novel therapeutic approach for Niemann-Pick disease, type C1.Molecular genetics and metabolism · 2021Article
- Climbing Fiber-Mediated Spillover Transmission to Interneurons Is Regulated by EAAT4.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits.Pharmacology & therapeutics · 2021Review
- Bidirectional learning in upbound and downbound microzones of the cerebellum.Nature reviews. Neuroscience · 2021Review
- Molecular Identity and Location Influence Purkinje Cell Vulnerability in Autosomal-Recessive Spastic Ataxia of Charlevoix-Saguenay Mice.Frontiers in cellular neuroscience · 2021Article
- Ablation of polyamine catabolic enzymes provokes Purkinje cell damage, neuroinflammation, and severe ataxia.Journal of neuroinflammation · 2020Article
- Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology.Journal of clinical medicine · 2020Review
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Authors and funding
9 authors at 5 institutions in 4 countries.
Funding
Abstract
Loss of excitatory amino acid transporters (EAATs) has been implicated in a number of human diseases including spinocerebellar ataxias, Alzhiemer's disease and motor neuron disease. EAAT4 and GLAST/EAAT1 are the two predominant EAATs responsible for maintaining low extracellular glutamate levels and preventing neurotoxicity in the cerebellum, the brain region essential for motor control. Here using genetically modified mice we identify new critical roles for EAAT4 and GLAST/EAAT1 as modulators of Purkinje cell (PC) spontaneous firing patterns. We show high EAAT4 levels, by limiting mGluR1 signalling, are essential in constraining inherently heterogeneous firing of zebrin-positive PCs. Moreover mGluR1 antagonists were found to restore regular spontaneous PC activity and motor behaviour in EAAT4 knockout mice. In contrast, GLAST/EAAT1 expression is required to sustain normal spontaneous simple spike activity in low EAAT4 expressing (zebrin-negative) PCs by restricting NMDA receptor activation. Blockade of NMDA receptor activity restores spontaneous activity in zebrin-negative PCs of GLAST knockout mice and furthermore alleviates motor deficits. In addition both transporters have differential effects on PC survival, with zebrin-negative PCs more vulnerable to loss of GLAST/EAAT1 and zebrin-positive PCs more vulnerable to loss of EAAT4. These findings reveal that glutamate transporter dysfunction through elevated extracellular glutamate and the aberrant activation of extrasynaptic receptors can disrupt cerebellar output by altering spontaneous PC firing. This expands our understanding of disease mechanisms in cerebellar ataxias and establishes EAATs as targets for restoring homeostasis in a variety of neurological diseases where altered cerebellar output is now thought to play a key role in pathogenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.