Ramesh Sharma Chiranjivi Neupane Thuy Linh Pham Miae Lee Sanghoon Lee So Yeong Lee 남민호 Cuk-Seong Kim Jin Bong Park 2024-01-12T06:32:23Z 2024-01-12T06:32:23Z 2023-11-23 2023-11 0270-6474 https://pubs.kist.re.kr/handle/201004/79746 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. English Society for Neuroscience Tonic Activation of NR2D-Containing NMDARs Exacerbates Dopaminergic Neuronal Loss in MPTP-Injected Parkinsonian Mice Article 10.1523/JNEUROSCI.1955-22.2023 1 Journal of Neuroscience, v.43, no.46, pp.7730 - 7744 Journal of Neuroscience 43 46 7730 7744 N scie scopus 001148065300003 Neurosciences Neurosciences & Neurology Article NIGRA PARS COMPACTA MOUSE SUBSTANTIA-NIGRA D-ASPARTATE RECEPTORS GLUTAMATE NEUROTOXICITY REGIONAL EXPRESSION BASAL GANGLIA NR2D SUBUNITS GOLGI CELLS HUMAN BRAIN MG2+ BLOCK dopaminergic neurons MPTP NR2D SNpc tonic NMDA