Endogenous retroviruses are associated with hippocampus-based memory impairment

Retrotransposons comprise a staggering 40% of the mammalian genome. Among them, endogenous retroviruses (ERV) represent sequences that closely resemble the proviruses created after exogenous retroviral infection. ERVs make up 8–10% of human and mouse genomes and range from evolutionarily ancient sequences to recent acquisitions. Studies in Drosophila have provided a causal link between genomic retroviral elements and cognitive decline. However, in mammals, the role of ERVs in learning and memory remains unclear. Here, we studied two independent murine models for ERV activation: muMT strain (lacking B cells and antibody production) and intracerebroventricular injection of streptozotocin (ICVI-STZ). We conducted behavioral assessments (contextual fear memory and spatial learning), as well as gene and protein analysis (RNA sequencing and PCR assays). Mice lacking mitochondrial-antiviral-signaling protein (MAVS) and mice lacking stimulator-of-interferon-genes protein (STING), two downstream sensors of ERV activation, provided confirmation of ERV impact. We found that muMT mice and ICVI-STZ mice induced hippocampal ERV activation as shown by increased gene and protein expression of the Gag sequence of the transposable element intracisternal A-particle (IAP). ERV activation was accompanied by significant hippocampus-related memory impairment in both models. Notably, deficiency of the MAVS pathway was protective against ICVI-STZ-induced cognitive pathology. Overall, our results demonstrate that ERV activation is associated with cognitive impairment in mice. Moreover, they provide a new molecular target for strategies aimed at attenuating retroviral element sensing, via MAVS, to treat dementia and neuropsychiatric disorders. Overall design: For figure 1, RNA-Seq was conducted from n = 2 muMT and n = 3 wildtype mice; for figure 3, n=3 ICVI-STZ and n=2 ICVI-STZ wildtype mice were analyzed 3 weeks after injection; for figure 3, n=3 ICVI-STZ and n=4 ICVI-STZ MAVS-KO mice were analyzed 3 weeks after injection