Regulation of Phosphorylated State of NMDA Receptor by STEP 61 Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress.

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 STEP ₆₁ (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 STEP ₆₁ activity. These changes are reduced partially with the STEP ₆₁ -inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP ₆₁ in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions.