RTL4, a retrovirus-derived gene implicated in autism spectrum disorder, is a microglial gene that responds to noradrenaline in the postnatal brain

RTL4, a gene acquired from a retrovirus, is a causative gene in autism spectrum disorder. Its KO mice exhibit increased impulsivity, impaired short-term spatial memory, failure to adapt to novel environments, and delayed noradrenaline (NA) recovery in the frontal cortex. However, due to its very low expression in the brain, it remains unknown which brain cells express RTL4 and its dynamics in relation to NA. Here, using knock-in mice carrying endogenous Rtl4 fused to Venus, we demonstrated that RTL4 is a microglial gene with several important properties. The RTL4-Venus fusion protein was detected as a secreted protein in the midbrain, hypothalamus, hippocampus and amygdala in the postnatal brain. Its signal intensity was high during critical periods of neonatal adaptation to novel environments and was upregulated by various stimuli, such as handling the mice, mild environmental changes and administration of isoproterenol, an agonist of adrenergic beta receptors. It was decreased by anesthesia but was maintained by the administration of milnacipran, an NA reuptake inhibitor. These results suggest that RTL4 intensity depends on the arousal state via NA and is somehow related to the NA reuptake process. In vitro mixed glial culture experiments demonstrated that Rtl4 is a microglial gene and suggested that RTL4 secretion responds rapidly to isoproterenol. Taken together with previous results from Rtl4 KO mice, microglial RTL4 plays an important role in the NA response and it is likely involved in the development of the NAergic neuronal network in the brain.