Upregulation of GAT1 expression as a mechanism for cognitive improvement after mGluR5 activation in traumatic brain injury

Abstract

Abstract Traumatic brain injury (TBI) significantly contributes mortality and disability worldwidely. However, cognitive deficits often accompany post-TBI neurological impairments. The metabotropic glutamate receptor 5 (mGluR5) is known to play a crucial role in cognitive-related disorders. Nevertheless, the specific impact of mGluR5 on cognitive impairment following TBI remains uncertain. In this study, we discovered that activating mGluR5 effectively mitigated cognitive impairment induced by Marmarou's weight-drop model of TBI and reduced the elevated levels of GABA content after TBI. Additionally, it was found that the activation of mGluR5 resulted in an upregulation of GABA transporter 1 (GAT1) expression, which had been downregulated after TBI in the brains of mice. Conversely, the inhibition of mGluR5 led to an upregulation of GAT1. And inhibiting GAT1 decreased the improvement of cognition after mGluR5 activation in Y-maze. Mechanistically, the activation of mGluR5 was found to decrease the level of RAB11A and upregulate the expression of p-ERK, CREB, and p-CREB after TBI. However, the inhibition of CREB reversed the decreased expression of RAB11A and the elevated expression of CREB, p-CREB, and GAT1. In summary, our research findings have shed light on the upregulation of active mGluR5 and its subsequent impact on GAT1 expression, resulting in a reduction of GABA levels and an improvement in cognitive impairment following TBI. Furthermore, we have identified the ERK/CREB/RAB11A pathway as a regulator of GAT1. These findings suggest that targeting mGluR5 may hold promise as a potential therapeutic strategy for enhancing cognition in individuals with TBI.