Impaired cortical neuronal homeostasis and cognition after diffuse traumatic brain injury are dependent on microglia and type I interferon responses

Abstract

Neuropsychiatric complications including depression and cognitive decline develop in the years after traumatic brain injury (TBI), negatively affecting quality of life. Microglial and type 1 interferon (IFN‐I) responses are associated with the transition from acute to chronic neuroinflammation after diffuse TBI in mice. Thus, the purpose of this study was to determine if impaired neuronal homeostasis and increased IFN‐I responses intersected after TBI to cause cognitive impairment. Here, the RNA profile of neurons and microglia after TBI (single nucleus RNA‐sequencing) with or without microglia depletion (CSF1R antagonist) was assessed 7 dpi. There was a TBI‐dependent suppression of cortical neuronal homeostasis with reductions in CREB signaling, synaptogenesis, and synaptic migration and increases in RhoGDI and PTEN signaling (Ingenuity Pathway Analysis). Microglial depletion reversed 50% of TBI‐induced gene changes in cortical neurons depending on subtype. Moreover, the microglial RNA signature 7 dpi was associated with increased stimulator of interferon genes (STING) activation and IFN‐I responses. Therefore, we sought to reduce IFN‐I signaling after TBI using STING knockout mice and a STING antagonist, chloroquine (CQ). TBI‐associated cognitive deficits in novel object location and recognition (NOL/NOR) tasks at 7 and 30 dpi were STING dependent. In addition, TBI‐induced STING expression, microglial morphological restructuring, inflammatory (Tnf, Cd68, Ccl2) and IFN‐related (Irf3, Irf7, Ifi27) gene expression in the cortex were attenuated in STINGKO mice. CQ also reversed TBI‐induced cognitive deficits and reduced TBI‐induced inflammatory (Tnf, Cd68, Ccl2) and IFN (Irf7, Sting) cortical gene expression. Collectively, reducing IFN‐I signaling after TBI with STING‐dependent interventions attenuated the prolonged microglial activation and cognitive impairment.

Cognitive impairment in Chinese traumatic brain injury patients: from challenge to future perspectives

“…This drives our strategy to limit TDP-43 overproduction to potentially provide therapeutic approaches to prevent the development of TBI-induced AD neuropathology. Recent research also has increasingly focused on the significant role of microglia in cognitive impairment post-TBI ( Willis et al, 2020 ; Krukowski et al, 2021 ; Bray et al, 2022 ; Packer et al, 2024 ). Common findings across these studies suggest that regulating microglia can reduce cognitive impairment after TBI, hinting at microglia as a potential breakthrough in future treatments for cognitive dysfunction post-TBI.…”

Deplete and repeat: microglial CSF1R inhibition and traumatic brain injury

“…Microglia depletion reversed suppression of these pathways and prevented the reduction in dendritic complexity at 7 DPI ( Witcher et al, 2021 ). One study investigated the effect of CSF1R inhibition before diffuse TBI using single nuclei sequencing at 7 DPI ( Packer et al, 2023 ). This study identified multiple subclusters, including deep-layer and upper layer cortical neurons.…”

“…TBI induced suppression of cortical neuronal homeostasis (reduction in synaptogenesis and CREB signaling). Microglia depletion before TBI was able to reverse approximately 50% of this gene expression across neuronal subclusters ( Packer et al, 2023 ).…”