Intrinsic Cellular Persistent Firing Sustains Hippocampal Spatial Representations during Working Memory

Neurons are the fundamental units of cognitive processing. The prevailing view holds that neurons are input-output units that fire action potentials only upon receiving sufficient synaptic input. Here, we demonstrate that this may not be the sole operational mode of neurons in vivo during cognitive tasks, by showing that hippocampal place cells actively maintain firing and preserve spatial information through molecularly defined intrinsic mechanisms. Using in vitro and in vivo recordings coupled with molecular manipulation in mice, we reveal that hippocampal persistent firing during spatial working memory is supported by individual neurons via TRPC4 ion channels. Despite the general belief that persistent activity carries working memory content, we demonstrate that this firing maintains immediate spatial representations and is required for spatial working memory performance. These findings redefine neurons as active contributors to information retention, beyond their traditional role as passive input-output units, potentially reshaping our general understanding of computation in the brain.