Artikel
Chemogenetic control of microcircuit activity in neurotrauma – neuroprotection and neuro-glial crosstalk
Chemogenetische Kontrolle der Aktivität von Mikroschaltkreisen bei Neurotrauma: Neuroprotektion und neuro-glialer Crosstalk
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Veröffentlicht: | 25. Mai 2022 |
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Gliederung
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Objective: To determine if chemogenetic control of neuronal microcircuitry modulates neuronal vulnerability and neuroinflammation in Traumatic Brain Injury (TBI)
Methods: We have used PSAM(Gly), PSAM(5HT and DREADD(Gq) chemogenetic systems to control the excitation of principal neurons and cortical microcircuits in a murine model of TBI. We have used genetically-encoded Calcium buffers to interfere with neuronal nuclear Calcium signaling.
Results: We demonstrated that PSAM-Gly-mediated inactivation of PV interneurons, applied in a limited time window after TBI, enhances the survival of principal neurons. This intervention is effective only when delivered within 24h of the trauma and it is associated with reduced astrogliosis. Conversely, PSAM-5HT-mediated over-activation of PV interneurons significantly worsens the secondary injury in the penumbra and increases astroglial scarring. However, complete depletion of PV interneurons generates a massive neuronal loss. Likewise, DREADD-Gq stimulation of principal neurons enhances the survival of cells in the penumbra, but activation of projecting axons from other cortical areas is ineffective. We used virus-delivered buffers of neuronal nuclear calcium to show that suppression of activity-related signals nuclear calcium and nuclear Ca/Calmodulin signals induce a massive increase in microglial reactivity with a Disease-Associated Microglia-like phenotype and is associated with a microglia-mediated synapse elimination and worse acute impairment. Transcriptome analysis new mediators of activity-dependent neuro-glial cross-talk; in particular, re-expression of osteoprotegerin in neurons is sufficient to reduce microglial reactivity and limit synaptic loss. Osteoprotegerin levels are elevated in the CSF of human TBI patients, indicating the translational value of our observations.
Conclusion: Chemogenetic manipulations of neuronal excitation in TBI demonstrate the need for neuronal activity to enhance neuronal survival and limit neuroinflammatory responses to brain damage. Thus, sustaining neuronal activity in the penumbra may constitute a new goal in acute neurotrauma treatment.