| Summary: | 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<sub>61</sub> (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<sup>+/−</sup> mice such a model. We performed TBI protocol using a controlled frontal impact device using C57BL/6 mice and SOD2<sup>+/−</sup> 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<sub>61</sub> activity. These changes are reduced partially with the STEP<sub>61</sub>-inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP<sub>61</sub> in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions.
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