Abstract
A fine balance between cell survival and cell death is required to sculpt the nervous system during development. However, an excess of cell death can occur following trauma, exposure to neurotoxins or alcohol, and some developmental and neurodegenerative diseases, such as Alzheimer's disease (AD). N-Methyl-D-aspartate receptors (NMDARs) support synaptic plasticity and survival of many neuronal populations whereas inappropriate activation may promote various forms of cell death, apoptosis, and necrosis representing the two extremes of a continuum of cell death processes both “in vitro” and “in vivo.” Hence, by identifying the switches controlling pro-survival vs. apoptosis and apoptosis vs. pro-excitotoxic outcome of NMDAR stimulation, NMDAR modulators could be developed that selectively block the cell death enhancing pro-survival signaling or synaptic plasticity mediated by NMDAR. Among these modulators, a role is emerging for the enzyme serine racemase (SR) that synthesizes D-serine, a key co-agonist with glutamate at NMDAR. This review summarizes the experimental evidence from “in vitro” neuronal cultures—with special emphasis on cerebellar granule neurons (CGNs)—and “in vivo” models of neurodegeneration, where the dual role of the SR/D-serine pathway as a master regulator of apoptosis and the apoptosis-necrosis shift will be discussed.
Highlights
Cell death is an obligatory process in the development, maintenance, and plasticity of the nervous system, and both anti-death and pro-death modulators are key elements in designing neural architecture
Cell death can manifest in many forms, which can be distinguished by various histological criteria “. . ., enzymological criteria, functional aspects or immunological characteristics. . . .” (Kroemer and Galluzzi, 2009)
N-Methyl-D-aspartate receptors (NMDARs) hypofunction or blockade in adult brain does not cause cell death, but rather damages the synapses, for example, by altering NMDAR subunit trafficking into dendritic spines (Aoki et al, 2003), decreasing dendritic spine density (Velázquez-Zamora et al, 2011), or impairing function and altering the morphology of dendritic spines, as in medium spiny neurons of corticostriatal slices treated with NR2A antagonist (Vastagh et al, 2012), which renders neurons more vulnerable to neurodegeneration
Summary
Reviewed by: Valerie Lynne Kilman, Northwestern University, USA Herman Wolosker, Technion, Israel. N-Methyl-D-aspartate receptors (NMDARs) support synaptic plasticity and survival of many neuronal populations whereas inappropriate activation may promote various forms of cell death, apoptosis, and necrosis representing the two extremes of a continuum of cell death processes both “in vitro” and “in vivo.”. By identifying the switches controlling pro-survival vs apoptosis and apoptosis vs pro-excitotoxic outcome of NMDAR stimulation, NMDAR modulators could be developed that selectively block the cell death enhancing pro-survival signaling or synaptic plasticity mediated by NMDAR. Among these modulators, a role is emerging for the enzyme serine racemase (SR) that synthesizes D-serine, a key co-agonist with glutamate at NMDAR.
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