Endogenous retroviruses are associated with hippocampus-based memory impairment

Area of Science:

• Genomics
• Neuroscience
• Immunology

Background:

• Retrotransposons, including endogenous retroviruses (ERVs), constitute a significant portion of mammalian genomes.
• While a link between genomic retroviral elements and cognitive decline is established in *Drosophila*, the role of ERVs in mammalian learning and memory remains largely unknown.

Purpose of the Study:

• To investigate the association between ERV activation and cognitive impairment in murine models.
• To explore potential molecular mechanisms and therapeutic targets for ERV-induced cognitive dysfunction.

Main Methods:

• Utilized two independent murine models: muMT strain and intracerebroventricular streptozotocin injection (ICVI-STZ).
• Conducted behavioral assessments including contextual fear memory and spatial learning.
• Performed gene and protein expression analysis (RNA sequencing, PCR, immunohistochemistry, Western blot) and utilized MAVS and STING knockout models.

Main Results:

• Both muMT and ICVI-STZ models showed hippocampal ERV activation, evidenced by increased Gag sequence expression of intracisternal A-particle.
• ERV activation correlated with significant hippocampus-dependent memory impairment in both models.
• Mice deficient in the MAVS pathway exhibited protection against ICVI-STZ-induced cognitive deficits.

Conclusions:

• Endogenous retroviral activation is demonstrably associated with cognitive impairment in mice.
• The MAVS pathway represents a potential molecular target for therapeutic strategies aimed at mitigating retroviral element sensing to treat dementia and neuropsychiatric disorders.