L1 retrotransposition alters the hippocampal genomic landscape enabling memory formation

•De novo L1 insertions occur in the adult hippocampus after exploration.•Blocking hippocampal L1 retrotransposition events prevents long-term memory formation.•Hippocampal L1 activity enables for long-term memory consolidation.

Somatic LINE-1 (L1) retrotransposition is a source of genomic mosaicism and potential phenotypic diversity among neurons during brain development. In the adult brain, L1 expression can be triggered by different environmental alterations, but its functional role in this context remains unknown. Here we demonstrate a neural activation-dependent increase in the number of L1 retrotransposon insertions in the hippocampus. Using both pharmacologic and genetic approaches in mice, we demonstrate that L1 expression in the adult hippocampus enables long-term memory formation. These results provide experimental evidence that L1 retrotransposition-induced genomic mosaicism is involved in cognitive processes such as memory formation.