MgSO4 alleviates anxiety-like behaviours in mice after traumatic brain injury by inhibiting astrocytic TRPM7 in the amygdala.

BACKGROUND: Reports indicate anxiety as one of the most prevalent mental modifications that occur following traumatic brain injury (TBI). Transient Receptor Potential Melastatin 7 (TRPM7) is extensively distributed throughout the nervous system. It regulates intracellular homeostasis of calcium and magnesium ions, regulates the functions of glial cells, including astrocytes in the central nervous system, influences the inflammatory cascade, and may play a significant role in anxiety pathogenesis. However, the potential of astrocytic TRPM7 in the treatment of TBI-induced anxiety remains largely unexplored. The magnesium ion (Mg2+) is an essential endogenous neuroprotective agent in the brain. A previous study has demonstrated that magnesium sulphate (MgSO4) can markedly reduce TBI-induced neuroinflammation and possess neuroprotective effects. Nevertheless, the efficacy of MgSO4 in alleviating anxiety is unclear. Therefore, this study utilised a rodent model of TBI to investigate whether MgSO4 could mitigate anxiety-like behaviours following mild TBI by inhibiting astrocytic TRPM7.

METHODS: Mild TBI was induced in male mice utilising the Feeney weight-drop paradigm with the rapid delivery of 2 μL of MgSO4 (100 mg/kg) into the left lateral ventricle. Behavioural and pathological changes were assessed at various time intervals following injury utilising neurological severity score, the elevated plus-maze (EPM) test, and the open field test (OFT). Molecular and structural modifications were examined using transcriptomic analysis, real-time quantitative polymerase chain reaction, local field potential recordings, and immunofluorescence staining.

RESULTS: Our findings revealed that mild TBI led to a diminished percentage of time spent in the central zone during the OFT, a reduced percentage of entries and time spent in the open arm during the EPM test, a decrease in the number of grid crossings, lowered serum Mg2+ levels, and a reduction in θ and γ power and θ-γ phase coupling. Additionally, there was a decrease in the intensity of PSD95 and synaptophysin in the amygdala, a reduction in MAP2 intensity in the amygdala, an increase in GFAP and Iba1 intensity in the amygdala, enhanced cytoskeletal hypertrophy and radial extension of astrocytes, along with heightened colocalization of TRPM7 with GFAP in the amygdala, and enhanced colocalization of IL-1β with GFAP. Notably, MgSO4 administration effectively reversed these pathological and functional deficits.

CONCLUSIONS: MgSO4 mitigates anxiety-like behaviours in mice after mild TBI by inhibiting astrocytic TRPM7 in the amygdala, indicating a potential therapeutic approach for post-TBI anxiety.