Changes in surface expression of N-methyl-D-aspartate receptors in the striatum in a rat model of Parkinson's disease
Jing Gan,1 Chen Qi,1 Li-Min Mao,2 Zhenguo Liu1
1Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; 2Department of Basic Medical Science, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
Background: N-methyl-D-aspartate (NMDA) receptors play a central role in glutamatergic synaptic transmission in the mammalian brain and are linked to the pathophysiology and symptomatology of Parkinson's disease (PD). However, changes in NMDA receptor expression in distinct subcellular compartments in PD have not been elucidated. In this study, we investigated changes in subcellular expression of NMDA receptors in striatal neurons in a rodent PD model.
Methods: Intracranial injection of the neurotoxin 6-hydroxydopamine (6-OHDA) was selectively lesioned into the nigrostriatal dopaminergic pathway in adult Sprague Dawley rats, which is a common rat model of PD. A surface receptor crosslinking assay was conducted to examine the response of individual NMDA receptor subunits to dopamine depletion in isolated and confined surface and intracellular compartments of striatal neurons.
Results: In PD rats where 6-OHDA was selectively lesioned, surface expression of NMDA receptor GluN1 subunits as detected by surface protein crosslinking assays was increased in the striatum. In contrast, intracellular levels of GluN1 were decreased in the lesioned region. The NMDA receptor GluN2B subunit was elevated in its abundance in the surface pool of the lesioned striatum, while intracellular GluN2B levels were not altered. GluN2A subunits in both surface and intracellular fractions remained stable. In addition, total cellular levels of striatal GluN1 and GluN2A were not changed in lesioned tissue, while total GluN2B proteins showed an increase.
Conclusion: These results demonstrate the differential sensitivity of principal NMDA receptor subunits to dopamine depletion. GluN1 and GluN2B expression in the distinct surface compartment underwent upregulation in striatal neurons after selective lesions of the dopaminergic pathway by 6-OHDA.
Keywords: glutamate, excitatory amino acid, NMDA, GluN, dopamine, 6-hydroxydopamine, caudate putamen, nucleus accumbens