Reduced GFAP Expression in Bergmann Glial Cells in the Cerebellum of Sigma-1 Receptor Knockout Mice Determines the Neurobehavioral Outcomes after Traumatic Brain Injury

Abstract

Neuroprotective effects of Sigma-1 receptor (S1R) ligands have been observed in multiple animal models of neurodegenerative diseases. Traumatic brain injury (TBI)-related neurodegeneration can induce long-lasting physical, cognitive, and behavioral disabilities. The aim of our study was to evaluate the role of S1R in the development of neurological deficits after TBI. Adult male wild-type CD-1 (WT) and S1R knockout (S1R-/-) mice were subjected to lateral fluid percussion injury, and behavioral and histological outcomes were assessed for up to 12 months postinjury. Neurological deficits and motor coordination impairment were less pronounced in S1R-/- mice with TBI than in WT mice with TBI 24 h after injury. TBI-induced short-term memory impairments were present in WT but not S1R-/- mice 7 months after injury. Compared to WT animals, S1R-/- mice exhibited better motor coordination and less pronounced despair behavior for up to 12 months postinjury. TBI induced astrocyte activation in the cortex of WT but not S1R-/- mice. S1R-/- mice presented a significantly reduced GFAP expression in Bergmann glial cells in the molecular layer of the cerebellum compared to WT mice. Our findings suggest that S1R deficiency reduces TBI-induced motor coordination impairments by reducing GFAP expression in Bergmann glial cells in the cerebellum.

Antidepressive-like Behavior-Related Metabolomic Signatures of Sigma-1 Receptor Knockout Mice

“…The metabolomic study showed that the serotonin concentration was increased in the plasma and brains of Sig1R KO mice, which was associated with reduced behavioral despair. This is in agreement with our previous study, in which CD-1 Sig1R KO mice did not develop depression-like behavior after traumatic brain injury during the 1-year follow-up monitoring [ 25 ]. Previous studies reported that C57BL/6J background Sig1R KO male mice exhibited a depressive-like phenotype [ 19 , 20 , 21 , 23 ].…”

“…The tail suspension test was performed at 2, 6, and 15 months of age to detect a depressive state in mice as described previously [ 25 , 32 ]. To prevent tail climbing behavior, a plastic tube (4 cm long) was put on each mouse’s tail.…”

“…There are a limited number of long-term phenotyping studies performed with CD-1 background Sig1R KO animals, and depression-related behavior has been poorly evaluated in these mice [ 9 ]. Recently, the first long-term study demonstrated that reduced behavioral despair could be a specific characteristic of CD-1 background Sig1R KO mice [ 25 ]. However, this was observed in Sig1R KO mice following TBI [ 25 ].…”

“…Recently, the first long-term study demonstrated that reduced behavioral despair could be a specific characteristic of CD-1 background Sig1R KO mice [ 25 ]. However, this was observed in Sig1R KO mice following TBI [ 25 ]. It is therefore essential to evaluate depression- and anxiety-related behavior at different ages in the same animals because mood-related disorders can develop over a lifetime [ 26 ].…”

Moderate traumatic brain injury triggers long-term risks for the development of peripheral pain sensitivity and depressive-like behavior in mice

“…These data are consistent with recently published results in mice suffering from progressive and severe depression-like behavior 6 months after CCI (16). Our previous findings revealed that moderate latFPI also induces depressive-like behavior in male CD-1 mice (21). However, there are also reports where depression-like behavior is not observed within 12 months after closed head injury (46).…”