Changes in microglia and TREM-2 expression in neonatal brain after hypoxia/ischemia in P7 mice

CHERTOFF, MARIELA; SHRIVASTAVA KALPANA; LLOVERA GEMMA; RECASENS MIREIA; GIMENEZ LLORT LYDIA; ACARIN LAIA

Conferencia; 8th Hershey Conference on developmental brain Injury; 2012

Perinatal brain injury is the underlying etiology for a host of developmental disabilities that includes spastic motor deficits and cognitive, behavioral and learning difficulties. Microglia is the main nervous component of the innate immune system, playing a role in inflammation and phagocytoses to repair the damage and maintain tissue homeostasis. Recently, patients with a loss-of-function mutation of the microglial innate immune receptor TREM2 had been shown to develop a chronic neurodegenerative disease, probably due to impaired tissue debris clearance. Reports demonstrate that TREM2-mediated phagocytic function of microglia is required for debris clearance and CNS tissue homeostasis. Hence, our aim is to characterize the expression of TREM2, in the control of neuroinflammation following hypoxia/ischemia (HI) in the newborn brain. We performed HI brain damage in postnatal day 7 (P7) C57/BL6 mice by permanent left carotid occlusion and litters were exposure for 55 minutes in a hypoxic chamber containing 8% of oxygen balanced with nitrogen, with controlled humidity and temperature maintained at 37ºC Pups were then returned to their dam until sacrifice. The age-matched controls and samples from 3 hours to 14 days after hypoxia were collected and processed for immunohistochemistry. We observed changes in the distribution pattern and morphology of microglia/macrophages (Iba-1+), not only in ischemic hemisphere (IL) but also in contralateral (CL) side as early as 3 hours post-hypoxia. The most affected regions in both hemispheres are the hippocampus and the subcortical white matter, showing maximum activated microglia after 72 hours post-hypoxia. However, morphologically activated Iba-1+ cells were observed only in the IL cortex, caudate-putamen and thalamus. Basal TREM2 expression was observed in the white matter and in the cingulum at P7 and P10. Following HI, an increase in TREM2 staining was observed in the subcortical white matter, hippocampus of both hemispheres, and in the caudate-putamen, cortex and thalamus in the IL hemisphere, following a similar expression pattern of microglia activation. In conclusion, massive microglia/macrophages activation and TREM2 expression in the IL hippocampus, corpus callosum and caudate-putamen is consistently shown. Remarkably, in the CL hippocampus and corpus callosum, milder atrophy is delayed in areas that show TREM2 expression and activation of microglia. These results suggest that the down regulation of TREM2 expression and microglia activation might be involved in the progression of the delayed tissue damage.