Sex-specific interneuron vulnerability after traumatic brain injury correlates with neurotrophic signaling and chloride homeostasis, independent of behavioral and network outcomes

Amandine Consumi¹Jérôme Laurin¹Michael K.E. Schäfer²Christophe Pellegrino¹Claudio Rivera^3,4*

• ¹INSERM U901 Institut de Neurobiologie de la Méditerranée, Marseille, Provence-Alpes-Côte d'Azur, France
• ²Department of Anaesthesiology, University Medical Center Mainz, Mainz, Germany
• ³INMED, Aix-Marseille Université, Marseille, France
• ⁴University of Helsinki, Helsinki, Uusimaa, Finland

This study investigates sex-specific behavioral, cognitive, electrophysiological, and molecular responses to traumatic brain injury (TBI) in mice, highlighting the importance of considering sex as a biological variable in TBI research. Locomotor abilities remained unaffected one-month post-injury in both sexes. While latency to enter the anxiogenic zone was significantly reduced in both sexes, female mice exhibited increased time in the open arms of the Elevated Plus Maze, suggesting sex-specific disinhibition and altered risk assessment following TBI. In the Barnes Maze, both sexes showed impaired spatial learning and memory retention after TBI, though female mice exhibited more pronounced early deficits but eventually recovered to baseline performance, whereas male mice retained persistent deficits. Electrophysiological recordings revealed sex-specific alterations in hippocampal oscillatory activity, with both sexes showing increased theta and alpha power post-TBI, but females displaying greater variability in rhythm dynamics. Notably, parvalbumin-positive (PV+) interneurons were significantly reduced in the hippocampus of female TBI mice, accompanied by upregulation of the pro-apoptotic neurotrophin receptor p75 NTR . Conversely, Brain-Derived Neurotrophic Factor (BDNF) expression was decreased in males but remained unchanged in females. Transcriptomic analyses identified femalespecific upregulation of genes involved in calcium signaling, inflammation, and neurogenesis, including CPNE3, SHISA3, GPR68, and LTK. Furthermore, chloride homeostasis showed sex-dependent alterations, with NKCC1 upregulated only in females.These findings reveal complex, sex-specific compensatory and pathological responses following TBI, emphasizing the need for sex-tailored therapeutic approaches.