# Evaluating Chronic Sex-Specific Changes in Glutamatergic Signaling Markers Following Traumatic Brain Injury

## TL;DR

This study shows that traumatic brain injury causes long-term, sex-specific changes in glutamate signaling, highlighting the need to consider sex in TBI treatments.

## Contribution

The study identifies chronic sex-specific alterations in glutamatergic signaling markers after TBI using a preclinical model.

## Key findings

- Proteomic analyses revealed sex-specific dysregulation of glutamatergic pathways and synaptic function.
- Immunofluorescence showed sex- and region-specific changes in NMDA receptor subunits and PSD95 in the hippocampus.
- Findings emphasize the importance of sex as a biological variable in TBI research and treatment development.

## Abstract

Traumatic brain injury (TBI) can lead to persistent adverse outcomes, including cognitive and emotional dysfunction, with recent estimates indicating that up to 50% of individuals with mild TBI experience long-term symptoms. Growing evidence suggests that biological sex influences TBI outcomes and recovery trajectories; however, the molecular underpinnings driving these sex-specific differences remain poorly understood. In this study, a preclinical TBI model was used to directly compare chronic glutamatergic alterations in adult male and female Sprague Dawley rats. To define frontocortical molecular signatures associated with sex-specific glutamatergic dysfunction, proteomic analyses were conducted. Proteomic data revealed dysregulation of key pathways, cellular processes, and molecular regulators involved in excitatory signaling and synaptic function in both sexes. Biomarker profiling identified a single common biomarker between males and females, along with multiple biomarkers unique to each sex. Furthermore, two key brain regions highly susceptible to TBI, the prefrontal cortex and hippocampal subregions, were examined for chronic alterations in key glutamatergic signaling proteins, including N-methyl-D-aspartate (NMDA) receptors and the excitatory synaptic marker postsynaptic density protein 95 (PSD95). Immunofluorescence analyses revealed both sex- and region-specific alterations in the expression of NMDA receptor subunits, as well as in PSD95. Notably, many of these changes were concentrated within the hippocampal subregions, suggesting long-term dysregulation of hippocampal glutamatergic circuitry following injury. Together, these findings indicate the emergence of chronic sex-specific pathophysiology in glutamate signaling after TBI and highlight the importance of incorporating sex as a biological variable in the development of precision medicine-based therapeutic strategies for TBI.