Long-Term Dynamic Changes of NMDA Receptors Following an Excitotoxic Challenge.

Alberto Granzotto,Stefano L Sensi,Valentina Gatta,Marco D’Aurora,Manuela Bomba,Marco Onofrj

doi:10.3390/cells11050911

Alberto Granzotto, Stefano L Sensi + Show 4 more

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https://doi.org/10.3390/cells11050911

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Abstract

Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons (also known as nNOS (+) neurons) are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (−) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a critical divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we indicate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings.

Highlights

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamatergic receptors primarily permeable to calcium ions (Ca2+ )
Early studies have demonstrated that nNOS (+) neurons are spared in post-mortem brain samples obtained from AD, HD, and PD patients [19–21], thereby indicating selective resilience to neurodegeneration
(D-2-amino-5- phosphonovaleric acid, 100 μM) to suppress glutamate-mediated effects demonstrated that changes in [Ca2+ ]i levels are driven by Ca2+ entry resulting from action potential firing and activation of synaptic glutamatergic receptors (Figure 1E)

Summary

Introduction

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamatergic receptors primarily permeable to calcium ions (Ca2+ ). NMDAR overstimulation generates a Ca2+ -dependent cascade of events encompassing PSD-95dependent recruitment and activation of nitric oxide synthase (nNOS) and the production of reactive oxygen species (ROS) of mitochondrial and non-mitochondrial origin [2,4]. NNOS-generated nitric oxide (NO) rapidly reacts with endogenous ROS (i.e., superoxide anion) to produce peroxynitrite (ONOO− ), which in turn mobilizes toxic amounts of intracellular zinc (Zn2+ ), leading to neuronal demise [2,5,6]. NADPH-diaphorase neurons ( known as nNOS (+) neurons) are a subpopulation of medium-sized aspiny interneurons spared following excitotoxic challenges [11–16]. This subpopulation is characterized by the naïve overexpression of the neuronal form of the enzyme nitric oxide synthase (nNOS, known as NOS1) [17,18]. Early studies have demonstrated that nNOS (+) neurons are spared in post-mortem brain samples obtained from AD, HD, and PD patients [19–21], thereby indicating selective resilience to neurodegeneration

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