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

Area of Science:

• Neuroscience
• Molecular Biology
• Traumatic Brain Injury Research

Background:

• Traumatic brain injury (TBI) frequently leads to persistent cognitive and emotional dysfunction, affecting up to 50% of mild TBI patients.
• Biological sex is increasingly recognized as a factor influencing TBI outcomes and recovery, yet the underlying molecular mechanisms are not well understood.

Purpose of the Study:

• To investigate chronic glutamatergic alterations in male and female rats following a preclinical TBI model.
• To identify sex-specific molecular signatures in the frontocortex related to glutamatergic dysfunction post-TBI.
• To examine sex- and region-specific changes in key glutamatergic proteins within the prefrontal cortex and hippocampus.

Main Methods:

• Utilized a preclinical TBI model in adult male and female Sprague Dawley rats.
• Conducted proteomic analyses to define frontocortical molecular signatures.
• Performed immunofluorescence analyses to assess alterations in N-methyl-D-aspartate (NMDA) receptors and postsynaptic density protein 95 (PSD95) in the prefrontal cortex and hippocampus.

Main Results:

• Proteomic analysis revealed dysregulated pathways in excitatory signaling and synaptic function in both sexes.
• Biomarker profiling identified unique and common molecular markers between males and females.
• Immunofluorescence showed sex- and region-specific alterations in NMDA receptor subunits and PSD95, particularly in hippocampal subregions.

Conclusions:

• Chronic, sex-specific pathophysiology in glutamate signaling emerges after TBI.
• Alterations are concentrated in hippocampal subregions, indicating long-term dysregulation of glutamatergic circuitry.
• Findings underscore the importance of considering sex as a biological variable for precision medicine in TBI therapeutics.