Role of NMDA Receptor-Mediated Glutamatergic Signaling in Chronic and Acute Neuropathologies

Abstract

N-Methyl-D-aspartate receptors (NMDARs) have two opposing roles in the brain. On the one hand, NMDARs control critical events in the formation and development of synaptic organization and synaptic plasticity. On the other hand, the overactivation of NMDARs can promote neuronal death in neuropathological conditions. Ca(2+) influx acts as a primary modulator after NMDAR channel activation. An imbalance in Ca(2+) homeostasis is associated with several neurological diseases including schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These chronic conditions have a lengthy progression depending on internal and external factors. External factors such as acute episodes of brain damage are associated with an earlier onset of several of these chronic mental conditions. Here, we will review some of the current evidence of how traumatic brain injury can hasten the onset of several neurological conditions, focusing on the role of NMDAR distribution and the functional consequences in calcium homeostasis associated with synaptic dysfunction and neuronal death present in this group of chronic diseases.

Figure 1

Implications of NMDAR in acute damage, ischemia/reperfusion. During ischemia, the overactivation of STEP induces the internalization of NMDARs, principally of GluN2B subunits, and the activation of extrasynaptic NMDAR triggers an excess of Ca²⁺ influx and excitotoxic events related to decreases in CREB activation and increases in calpain activity. During reperfusion, injury induces the generation of ROS and ONOO⁻. The increase of ONOO⁻ alters the activity of glutamate transporter in astrocytes. The excess glutamate leads to the overactivation of NMDARs.

Figure 2

Dysregulation of NMDARs performance in neuropsychiatric disorders and in acute damage. (a) Schematic of the role of NMDARs in TBI and neurodegenerative disease. Under physiological conditions, synaptic NMDARs are activated as well as antiapoptotic cell pathways preventing excitotoxicity by targeting CREB. After acute damage, including TBI, there is a decrease in CREB activation, increased activation of extrasynaptic NMDARs, and ROS/NOS generation. In neurological disorders such as AD, there are alterations in cell signaling due to misfolding proteins, microtubule depolymerization, excessive Ca²⁺ influx, ROS generation, and excitotoxicity. The cell death mechanisms associated with glutamatergic transmission include calpains, PTEN, and DAPK1. (b) Hypothesized interaction between TBI, neurological diseases, and “normal” aging. The progression curves show the age of patients at disease onset and the severity of neurological symptoms. The black line shows the progression of neurodegeneration in normal aging and the red line shows the acceleration of neurodegeneration that occurs in diseases such as AD. This neurodegeneration includes neuroinflammation, oxidative stress markers accumulation, and the aggregation of misfolded proteins. This neurodegeneration can be accelerated after TBI both in “normal aging” (blue line) and in patients with neurodegenerative disease (purple line).