NeuropharmacologyJul 1, 2021

Lower levels of a brain support cell glutamate transporter in the lateral habenula linked to depression-like behavior in a rat Parkinson’s model

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Updated Apr 3, 2026

Abstract

Unilateral lesions of the substantia nigra in rats resulted in increased glutamate levels in the lateral habenula (LHb) and induced depressive-like behaviors.

Dysfunction of the astroglial glutamate transporter GLT-1 may be linked to hyperactivity of neurons in the LHb.
Lesioned rats exhibited lower doses of GLT-1 inhibitor WAY-213613 to induce depressive-like behaviors compared to sham-lesioned rats.
Injection of WAY-213613 increased the firing rate of LHb neurons and extracellular levels of glutamate in both groups.
The excitatory effects of WAY-213613 lasted longer in lesioned rats than in sham-lesioned rats.
Bioinformatics analysis indicated that GLT-1 is associated with various biomarkers of Parkinson's disease and depression risks.

Simplified

Recent studies show that neuron-glial communication plays an important role in neurological diseases. Particularly, dysfunction of astroglial glutamate transporter GLT-1 has been involved in various neuropsychiatric disorders, including Parkinson's disease (PD) and depression. Our previous studies indicated hyperactivity of neurons in the lateral habenula (LHb) of hemiparkinsonian rats with depressive-like behaviors. Thus, we hypothesized that impaired expression or function of GLT-1 in the LHb might be a potential contributor to LHb hyperactivity, which consequently induces PD-related depression. In the study, unilateral lesions of the substantia nigra pars compacta (SNc) by 6-hydroxydopamine in rats induced depressive-like behaviors and resulted in neuronal hyperactivity as well as increased glutamate levels in the LHb compared to sham-lesioned rats. Intra-LHb injection of GLT-1 inhibitor WAY-213613 induced the depressive-like behaviors in both groups, but the dose producing behavioral effects in the lesioned rats was lower than that of sham-lesioned rats. In the two groups of rats, WAY-213613 increased the firing rate of LHb neurons and extracellular levels of glutamate, and these excitatory effects in the lesioned rats lasted longer than those in sham-lesioned rats. The functional changes of the GLT-1 which primarily expresses in astrocytes in the LHb may attribute to its downregulation after degeneration of the nigrostriatal pathway. Bioinformatics analysis showed that GLT-1 is correlated with various biomarkers of PD and depression risks. Collectively, our study suggests that astroglial GLT-1 in the LHb regulates the firing activity of the neurons, whereupon its downregulation and dysfunction are closely associated with PD-related depression.

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Lower levels of a brain support cell glutamate transporter in the lateral habenula linked to depression-like behavior in a rat Parkinson’s model

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