THE ACTIVATED MICROGLIA AND IMPAIRED GLUTAMATERGIC NEUROTRANSMISSION VIA UPREGULATING THE TNF-A/TNFR1 SIGNALING PATHWAY IN THE MICE EXPOSED TO REPEATED SOCIAL DEFEAT STRESS AS JUVENILES
Authors: Yoshida *Mikio , Katada Hikari , Isozumi Yuya , Kawai Shunya , Kushima Itaru , Yoshimi Akira , Ozaki Norio , Noda Yukihiro 
Published: February 2025

Abstract

Background
Exposure to psychosocial stress (e.g. bullying) in juveniles is one of risk factors as development of stress-related psychiatric disorders, especially with treatment-resistant, later in life. Exposures to repeated psychosocial stress activates microglia, which are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. An abnormality of the glutamatergic neurotransmissions is a common event in the pathophysiology of these diseases. However, it is unclear whether exposure to psychosocial stress as juveniles is affected to brain immunity and glutamatergic systems.

Objective
The present study was investigated the inflammatory responses and glutamatergic neurotransmission in brain in the mice exposed to social defeat stress as juveniles.

Methods
Juvenile (3-week-old) male C57BL/6J mice were exposed to single or repeated (for 10 days) social defeat stress, and subjected to the social interaction test on the next day of the last stress exposure. R-7050, an inhibitor of TNF-α signaling, was intraperitoneally administered 30 min before every exposure to the stress exposure. The expression of comprehensive gene using DNA microarray analysis, expression of TNF-α, IL-6, or PGE2 using ELISA, and expression intensity of Iba-1 using immunostaining were analyzed in the PFC of mice 2 or 3 hr after the last stress exposure. Ability to release glutamate was analyzed by in vivo microdialysis, on the next day of the last stress exposure.

Results
The mice exposed to repeated social defeat stress as juveniles showed the impairment of social behaviors in consistent with previously [1, 2]. In the mice showing social behavioral impairment, especially mice exposed to repeated social defeat stress, the expression changes of inflammation- or immune system-related genes were remarkable in the PFC, compared to those in control (non-defeated) mice. The expression level of TNF-α and expression of Iba-1 were significantly increased in the PFC of repeated stress mice, compared to control mice. However, such neurochemical changes were not observed in mice exposed to single social defeat stress. The mice exposed to repeated stress also showed the impairment of high potassium (K+)-induced extracellular glutamate release, high potassium (K+)-induced extracellular glutamate release. When R-7050 was given during every repeated stress exposure, impairments of behavioral impairment, glutamatergic transmission impairment, and Iba-1intensity change were prevented.

Discussion & Conclusion
Our results suggest that activation of brain immunity induced by exposure to repeated, but not single (acute) social defeat stress plays an important role in the social behavioral impairment. The activation of microglia through TNF-α/TNFR1-madiated signaling pathway was involved in development of behavior impairment and glutamatergic neurotransmission abnormality. Activation of brain immunity may contribute to the pathophysiology of treatment-resistant stress-related psychiatric disorders in adolescents with adverse juvenile experiences, because the behavior impairment in this model mice failed to affect antidepressants as sertraline [3].

References
[1]Yoshida et al., Neuropharmacology. 2022. 217:109208.
[2]Hasegawa et al., Neuropharmacology. 2019. 148:107-116.
[3]Hasegawa et al., Int J Neuropsychopharmacol. 2018. 21(9):837-846.