Brief sleep disruption following hippocampus-dependent learning downscales interneuron synapses within lateral entorhinal cortex

Abstract

Study objectivesBrief sleep loss alters cognition and the function of the hippocampus, but it is unclear how it affects neocortical input to hippocampus. We tested how synaptic structures of SST+ interneurons in lateral and medial entorhinal cortex (LEC and MEC), which are the major neocortical inputs to hippocampus, are affected by brief sleep deprivation (SD) in the hours following learning. MethodsWe used Brainbow 3.0 to label LEC or MEC SST+ interneurons in male mice. We compared their synaptic structures after single trial contextual fear conditioning (CFC) followed by either a 6-h period of ad lib sleep, or gentle handling SD. We also immunohistochemically characterized activity-dependent cFos expression in EC SST-neurons and SST+ interneurons after post-CFC sleep or SD. ResultsPost-CFC SD caused dramatic alterations in dendritic spine type distributions and reduced spine size in LEC - but not MEC - after post-CFC SD. In contrast, SD significantly reduced overall dendritic spine density in MEC, but not LEC, SST+ interneurons, without corresponding changes in spine type or size. In both EC subregions, SD increased the relative expression of cFos in SST- neurons vs. SST+ interneurons, driven primarily by reduced cFos expression in SST+ interneurons. ConclusionsOur data suggest that excitatory synaptic input to SST+ interneurons is reduced in EC after SD, with effects that differ quantitatively and qualitatively between LEC and MEC. Our findings suggest that sleep loss disrupts hippocampus-dependent memory processing in part through altered excitatory/inhibitory balance in EC structures providing input to hippocampus. Significance StatementChanges to the function of somatostatin-expressing (SST+) interneurons have been implicated in the etiology of psychiatric and neurological disorders in which both cognition and sleep behavior are affected. Here, we measure the effects of very brief experimental sleep deprivation on synaptic structures of SST+ interneurons in entorhinal cortex - a brain structure that provides input to the hippocampus and is critical for sleep-dependent memory processing. We find that only six hours of post-learning sleep deprivation restructures SST+ interneurons dendritic spines, causing dramatic, subregion-specific reductions in dendritic spine size, morphological type, and density. These changes have the potential to dramatically alter excitatory/inhibitory balance and the regulation of neocortical input to hippocampus, leading to cognitive disruptions commonly associated with sleep loss.