Regulation of Phosphorylated State of NMDA Receptor by STEP61 Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress.

Francisco J Carvajal,Waldo Cerpa

doi:10.3390/antiox10101575

Abstract

Traumatic Brain Injury (TBI) mediates neuronal death through several events involving many molecular pathways, including the glutamate-mediated excitotoxicity for excessive stimulation of N-methyl-D-aspartate receptors (NMDARs), producing activation of death signaling pathways. However, the contribution of NMDARs (distribution and signaling-associated to the distribution) remains incompletely understood. We propose a critical role of STEP61 (Striatal-Enriched protein tyrosine phosphatase) in TBI; this phosphatase regulates the dephosphorylated state of the GluN2B subunit through two pathways: by direct dephosphorylation of tyrosine-1472 and indirectly via dephosphorylation and inactivation of Fyn kinase. We previously demonstrated oxidative stress’s contribution to NMDAR signaling and distribution using SOD2+/− mice such a model. We performed TBI protocol using a controlled frontal impact device using C57BL/6 mice and SOD2+/− animals. After TBI, we found alterations in cognitive performance, NMDAR-dependent synaptic function (decreased synaptic form of NMDARs and decreased synaptic current NMDAR-dependent), and increased STEP61 activity. These changes are reduced partially with the STEP61-inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP61 in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions.

Highlights

IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Antioxidants 2021, 10, 1575 case, we studied the effect of frontal impact close-head injury, the most frequent cause of Traumatic brain injury (TBI) [8], on the hippocampal glutamatergic transmission and the functional consequences in a murine model of mild repetitive TBI, focusing our attention on the regulation and functionality of N-methyl-D-aspartate receptors (NMDARs)
As we have found a decrease in the response corresponding to NMDARs, we decided to analyze changes in the distribution of NMDARs between synaptic and extrasynaptic regions that could contribute to the neuropathological effects observed after brain trauma in WT and SOD2+/− mice (Figure 4B)

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Traumatic brain injury (TBI) is a structural and physiological disruption of brain function resulting from an external force. It is one of the leading causes of death and disability in industrialized countries [1]. Patients suffer from surface contusion, focal damage, and intracranial hemorrhages. This primary damage immediately generates damage to the brain, making a possible window of clinical/therapeutic intervention unfeasible

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