Abstract: Introduction: Traumatic brain injury (TBI) entails a strong neuronal excitation/inhibition imbalance and a severe immune response mediated among others by microglia. A possible link between the excitation/inhibition imbalance and microglia response is nuclear calcium signalling, an activity dependant program regulating transcriptional responses. In this study1, we investigate the effects neuronal nuclear calcium signalling has on the microglial response during TBI. Methods: Parvalbumin, a nuclear-tagged calcium-buffer, was expressed in mice neurons buffering nuclear calcium signalling. After TBI microglial response and neuronal / synaptic density was assessed using immunohistochemistry and transcriptome analysis. Behavioural effects were measured by quantifying spontaneous whisking. Neuronal OPG expression was verified after chemogenetic inhibition of parvalbumin interneurons using a PSAM/PSEM system. Results: Buffering neuronal nuclear calcium signalling during trauma persistently increased microglia density, expressing phagocytic and Disease-Associated-Microglia (DAM) markers. Furthermore, this model s whisking activity and excitatory synaptic density were significantly reduced. Transcription analysis showed that neuronal nuclear calcium buffering upregulates inflammatory responses (complement factors, chemokines, DAM markers, interferon response) while downregulating epigenetic regulators and synaptic genes during TBI. Neuronal OPG is a nuclear calcium dependant mediator and overexpression decreases microglia infiltration and synaptic loss during trauma. Its upregulation in the CSF of human TBI patients makes OPG a translational target. Conclusion: Neuronal nuclear calcium signalling is able to regulate Neuron-Microglia crosstalk and the neuroinflammatory cascade during TBI in parts through OPG, which is expressed by neurons in an activity dependent manner and able to restrict microglial infiltration and synaptic loss.
Processing Request
No Comments.