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EAAT2 Activation Regulates Glutamate Excitotoxicity and Reduces Impulsivity in a Rodent Model of Parkinson’s Disease
Journal article   Open access   Peer reviewed

EAAT2 Activation Regulates Glutamate Excitotoxicity and Reduces Impulsivity in a Rodent Model of Parkinson’s Disease

Sandhya Kortagere, Sanjay Das, Kyle Mccloskey and Binod Nepal
Molecular neurobiology
04 Dec 2024
DOI: https://doi.org/10.1007/s12035-024-04644-0
PMID: 39630405
Featured in Collection :   Research Supported by Drexel Libraries' OA Programs
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https://doi.org/10.1007/s12035-024-04644-0View
Published, Version of Record (VoR)Open Access via Drexel Libraries Read and Publish Program 2024CC BY V4.0,  Open

Abstract

5CSRTT Cognitive impairment EAAT2 Impulsivity NMDA receptor subunits Parkinson's disease Cognitive Development or Processes Parkinsons Disease
Parkinson’s disease (PD) is a systemic disease characterized by motor and nonmotor impairments. Loss of dopaminergic neurons in the substantia nigra pars compacta region in PD disrupts dopamine-glutamate homeostasis in the corticostriatal circuit, contributing to cognitive impairment. In addition, excitatory amino acid transporter-2 (EAAT2), localized predominantly to astrocytes and responsible for > 80% of synaptic glutamate clearance, is downregulated in PD, causing glutamate spillover and excitotoxicity. This altered dopamine-glutamate homeostasis and excitotoxicity may affect reward-mediated decision-making behaviors and promote impulsive behaviors in PD. In this study, we hypothesized that GTS467, a small-molecule activator of EAAT2, could effectively reduce excitotoxicity and treat cognitive impairment without promoting impulsive behavior in PD. Rats that were unilaterally lesioned with the 6-OHDA toxin to produce Parkinsonian symptoms were referred to as lesioned rats. Lesioned rats were trained to meet baseline criteria in a 5-choice serial reaction time task, and the chronic effects of GTS467 were assessed after 3 weeks of treatment. The results showed that chronic treatment with GTS467 significantly improved correct responses and reduced premature impulsive responses and omissions compared with saline treatment. This improvement in performance correlated with a reduction in glutamate levels, an increase in EAAT2 expression, and normalization of NMDA receptor subunit expression and signaling. Furthermore, transcriptomic studies on the prefrontal cortex tissue have shown the differential expression of genes involved in neuroprotection, neuroinflammation, learning, and memory. These results validate the role of glutamate excitotoxicity in promoting impulsive behaviors and suggest that GTS467 can be developed as a therapeutic agent to reduce cognitive impairment and impulsive behaviors in PD.

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8 citations in Web of Science
4 citations in Scopus

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