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Research Articles, Cellular/Molecular

Tonic Activation of NR2D-Containing NMDARs Exacerbates Dopaminergic Neuronal Loss in MPTP-Injected Parkinsonian Mice

Ramesh Sharma, Chiranjivi Neupane, Thuy Linh Pham, Miae Lee, Sanghoon Lee, So Yeong Lee, Min-Ho Nam, Cuk-Seong Kim and Jin Bong Park
Journal of Neuroscience 15 November 2023, 43 (46) 7730-7744; DOI: https://doi.org/10.1523/JNEUROSCI.1955-22.2023
Ramesh Sharma
1Department of Biomedicine, Chungnam National University, Daejeon 35015, Republic of Korea
2Physiology, Chungnam National University, Daejeon 35015, Republic of Korea
3Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08852, Republic of Korea
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Chiranjivi Neupane
1Department of Biomedicine, Chungnam National University, Daejeon 35015, Republic of Korea
2Physiology, Chungnam National University, Daejeon 35015, Republic of Korea
3Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08852, Republic of Korea
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Thuy Linh Pham
1Department of Biomedicine, Chungnam National University, Daejeon 35015, Republic of Korea
2Physiology, Chungnam National University, Daejeon 35015, Republic of Korea
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Miae Lee
2Physiology, Chungnam National University, Daejeon 35015, Republic of Korea
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Sanghoon Lee
3Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08852, Republic of Korea
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So Yeong Lee
3Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08852, Republic of Korea
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Min-Ho Nam
4Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
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Cuk-Seong Kim
1Department of Biomedicine, Chungnam National University, Daejeon 35015, Republic of Korea
2Physiology, Chungnam National University, Daejeon 35015, Republic of Korea
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Jin Bong Park
3Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08852, Republic of Korea
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Abstract

NR2D subunit-containing NMDA receptors (NMDARs) gradually disappear during brain maturation but can be recruited by pathophysiological stimuli in the adult brain. Here, we report that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication recruited NR2D subunit-containing NMDARs that generated an Mg2+-resistant tonic NMDA current (INMDA) in dopaminergic (DA) neurons in the midbrain of mature male mice. MPTP selectively generated an Mg2+-resistant tonic INMDA in DA neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). Consistently, MPTP increased NR2D but not NR2B expression in the midbrain regions. Pharmacological or genetic NR2D interventions abolished the generation of Mg2+-resistant tonic INMDA in SNpc DA neurons, and thus attenuated subsequent DA neuronal loss and gait deficits in MPTP-treated mice. These results show that extrasynaptic NR2D recruitment generates Mg2+-resistant tonic INMDA and exacerbates DA neuronal loss, thus contributing to MPTP-induced Parkinsonism. The state-dependent NR2D recruitment could be a novel therapeutic target for mitigating cell type-specific neuronal death in neurodegenerative diseases.

SIGNIFICANCE STATEMENT NR2D subunit-containing NMDA receptors (NMDARs) are widely expressed in the brain during late embryonic and early postnatal development, and then downregulated during brain maturation and preserved at low levels in a few regions of the adult brain. Certain stimuli can recruit NR2D subunits to generate tonic persistent NMDAR currents in nondepolarized neurons in the mature brain. Our results show that MPTP intoxication recruits NR2D subunits in midbrain dopaminergic (DA) neurons, which leads to tonic NMDAR current-promoting dopaminergic neuronal death and consequent abnormal gait behavior in the MPTP mouse model of Parkinson's disease (PD). This is the first study to indicate that extrasynaptic NR2D recruitment could be a target for preventing neuronal death in neurodegenerative diseases.

  • dopaminergic neurons
  • MPTP
  • NR2D
  • SNpc
  • tonic NMDA

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The Journal of Neuroscience: 43 (46)
Journal of Neuroscience
Vol. 43, Issue 46
15 Nov 2023
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Tonic Activation of NR2D-Containing NMDARs Exacerbates Dopaminergic Neuronal Loss in MPTP-Injected Parkinsonian Mice
Ramesh Sharma, Chiranjivi Neupane, Thuy Linh Pham, Miae Lee, Sanghoon Lee, So Yeong Lee, Min-Ho Nam, Cuk-Seong Kim, Jin Bong Park
Journal of Neuroscience 15 November 2023, 43 (46) 7730-7744; DOI: 10.1523/JNEUROSCI.1955-22.2023

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Tonic Activation of NR2D-Containing NMDARs Exacerbates Dopaminergic Neuronal Loss in MPTP-Injected Parkinsonian Mice
Ramesh Sharma, Chiranjivi Neupane, Thuy Linh Pham, Miae Lee, Sanghoon Lee, So Yeong Lee, Min-Ho Nam, Cuk-Seong Kim, Jin Bong Park
Journal of Neuroscience 15 November 2023, 43 (46) 7730-7744; DOI: 10.1523/JNEUROSCI.1955-22.2023
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Keywords

  • dopaminergic neurons
  • MPTP
  • NR2D
  • SNpc
  • tonic NMDA

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