Expanding Hippocampal Ensembles through LINE-1 RNA Downregulation Enhances Cognition

Abstract

Episodic memories are encoded through the activation of small overlapping neuronal ensembles, a coding principle that ensures efficient encoding and high memory capacity. While cellular excitability is known to drive the allocation of select hippocampal neurons into these ensembles, the underlying molecular mechanisms remain elusive. Here, an epigenetic-functional analysis of hippocampal dentate granule cells revealed robust nuclear expression of RNA from autonomous LINE-1 retrotransposons, with significantly lower LINE-1 RNA levels in environmentally activated neurons compared to non-activated counterparts. Knockdown of LINE-1 RNA in the dentate gyrus increased action potential firing capacity and expanded the number of environmentally activated cells, indicating that LINE-1 expression is inversely correlated with ensemble eligibility. LINE-1 RNA knockdown enhanced spatial working memory at the expense of pattern separation, a trade-off consistent with expanded dentate gyrus ensembles and diminished sparse coding. Together, these findings demonstrate that nuclear LINE-1 RNA was co-opted during evolution to control ensemble eligibility in dentate granule cells, a novel postmitotic neuronal function for LINE-1 RNA that restricts ensemble size to preserve sparse coding and support pattern separation.