MERTK-related engulfment of norepinephrinergic neuronal presynaptic membrane by astrocytes following acute TBI and potentiation effect of peripheral nerve modulation.

OBJECTIVES

The study investigated the locus coeruleus (LC) changes after acute traumatic brain injury (TBI) and the effects of peripheral nerve modulation (PNM) in a mouse model.

METHODS

We performed closed controlled impact to simulate TBI in mice. We adopted electrical stimulation of the right median nerve as a method of PNM. Low-frequency and high-frequency peripheral nerve modulation (LF-PNM and HF-PNM) were administered on the 1st, 2nd, and 3rd days after the injury. We conducted a cell interaction analysis on the single-cell data of the mouse brainstem from the previous stage. Meanwhile, we also performed arousal and stress behavioral tests, immunofluorescence staining for apoptosis and activation of LC norepinephrinergic neurons, and examination of astrocytic phagocytosis in association with MERTK expression.

RESULTS

Acute TBI induced apoptosis of LC norepinephrinergic neurons alongside behavioral impairments. TBI triggered reactive astrogliosis in the LC, with elevated GFAP-Lamp2 colocalization. Increased GFAP-NET colocalization indicated astrocytic engulfment of presynaptic membrane proteins from norepinephrinergic neurons. Cell interaction analysis identified MERTK-mediated astrocyte-norepinephrinergic neuron crosstalk; GFAP-MERTK immunofluorescence confirmed spatially increased astrocytic MERTK expression linked to NET phagocytosis. LF-PNM further enhanced astrocytic phagocytosis of LC norepinephrinergic presynaptic proteins after TBI, reduced neuronal apoptosis, facilitated neuronal activation, and rescued arousal and stress functions.

CONCLUSION

After acute TBI, LC astrocytes phagocytose norepinephrinergic presynaptic proteins via MERTK. LF-PNM enhances this process, improving post-TBI arousal and stress dysfunction.