IFN-I Response and TREM2 Receptor Are Major Modulators of Microglial and Synaptic Dysfunctions in a Model of Neurodevelopmental Disease

Microglia are highly dynamic cells that patrol the brain parenchyma and shape the continuously changing brain environment. They are involved in different aspects of neurodevelopment and express the Triggering Receptor Expressed on Myeloid Cell 2 (TREM2) which has pivotal roles in microglial phagocytosis and synapse elimination. Genetic and environmental triggers may profoundly alter these finely tuned developmental processes by modifying microglial and neuronal functionality. As a consequence, early dysfunctions in physiological neuro-immune pathways may eventually lead to neurodevelopmental disorders in the newborn. Our bulk RNAseq analysis on hippocampi and pre-frontal cortices from Trem2+/+ and Trem2-/- mice revealed that the differentially expressed genes in Trem2-/- young mice displayed a significant association with schizophrenia (SCZ). Based on these findings, we aimed at dissecting the molecular and transcriptional pathways connecting maternal viral infections and TREM2 dysfunction in schizophrenia. To this purpose, we took advantage of a well-established Maternal immune Activation (MIA) model in which pregnant dams are injected with the viral analog polyriboinosinic-polyribocytidilic acid (PolyIC). Wild type (WT) offspring derived from PolyIC injected dams (here referred as PolyIC offspring) and analyzed at post-natal day (P) 18 showed defective excitatory synapses, a hallmark of SCZ, together with decreased microglial synaptic engulfment in the hippocampus. Also, PolyIC WT offspring displayed decreased TREM2 protein level in the brain. To better dissect the role of TREM2 in the manifestation of SCZ induced by viral infections during pregnancy, we applied the PolyIC model of MIA to genetically modified mice, lacking one (Trem2+/-) or two copies (Trem2-/-) of TREM2 receptor. Trem2+/- and Trem2-/- PolyIC offspring analyzed at P18 did not display alterations in synaptic density and microglia phagocytic capacity as shown for WT (Trem2+/+) PolyIC offspring. These data demonstrate that TREM2 expression is central for the manifestation of PolyIC-mediated neuro-microglia dysfunctions in the context of neurodevelopmental disorders. To define the underlying transcriptional mechanisms, we run bulk RNAseq analysis on Trem2+/+, Trem2+/- and Trem2-/- microglia treated with PolyIC in vitro. We observed that Trem2-/- microglia display downregulated expression of genes involved in cytokines, proteasome and Type I interferon (IFN-I) responses upon PolyIC challenge. To establish a connection between IFN-I response and TREM2 dysregulation in the PolyIC model of MIA, we blocked IFN-I signaling in pregnant dams prior to PolyIC administration. Interfering with IFN-I response was sufficient to rescue excitatory synaptic downregulation and restore microglial membrane-bound TREM2 and soluble TREM2 levels, without however rescuing the defective microglia engulfment ability. Our data highlight that TREM2 receptor is a central hub downstream the IFN-I cascade triggered by MIA. These findings open the possibility that modulating TREM2 and its soluble form may positively impact on the pathological course. Unveiling the role of the receptor and the downstream pathways will shed light on new mechanisms and will help identifying new targets in neurodevelopmental pathologies like SCZ.