Havekes et al. Sleep Deprivation Causes Memory Deficits by Negatively Impacting Neuronal Connectivity in Hippocampal Area CA1

Robbert Havekes1,2*, Alan J Park1†, Jennifer C Tudor1, Vincent G Luczak1, Rolf T Hansen1, Sarah L Ferri1, Vibeke M Bruinenberg2, Shane G Poplawski1, Jonathan P Day3, Sara J Aton4, Kasia Radwan´ ska5, Peter Meerlo2, Miles D Houslay6, George S Baillie3, Ted Abel1*

1Department of Biology, University of Pennsylvania, Philadelphia, United States; 2Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, The Netherlands; 3Institute of Cardiovascular and Medical Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; 4LSA Molecular, Cellular, and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States; 5Laboratory of Molecular Basis of Behavior, Head Nencki Institute of Experimental Biology, Warsaw, Poland; 6Institute of Pharmaceutical Science, King’s College London, London, United Kingdom

 Abstract

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK- cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density.

DOI: 10.7554/eLife.13424.001

Introduction

Sleep is a ubiquitous phenomenon and most species, including humans, spend a significant time asleep. Although the function of sleep remains unknown, it is widely acknowledged that sleep is cru- cial for proper brain function. Indeed, learning and memory, particularly those types mediated by the hippocampus, are promoted by sleep and disrupted by sleep deprivation (Havekes et al., 2012a; Abel et al., 2013; Whitney and Hinson, 2010). Despite the general consensus that sleep deprivation impairs hippocampal function, the molecular signaling complexes and cellular circuits by which sleep deprivation leads to cognitive deficits remain to be defined.

The alternation of wakefulness and sleep has a profound impact on synaptic function, with changes observed in synaptic plasticity and transmission (Havekes et al., 2012a; Abel et al., 2013;

eLife digest The demands of modern society means that millions of people do not get sufficient sleep on a daily basis. Sleep deprivation, even if only for brief periods, can impair learning and memory. In many cases, this impairment appears to be related to changes in the activity of a brain region called the hippocampus. However, the exact processes responsible for producing the effects of sleep deprivation remain unclear.

During learning or forming a new memory, the connections between the relevant neurons in the brain change. Havekes et al. found that depriving mice of sleep for just five hours dramatically reduced the connectivity between neurons in the hippocampus. This reduction is caused by the increased activity of cofilin, a protein that breaks down the actin filaments that shape the connections between neurons.

Havekes et al. then used a virus to introduce an inactive version of cofilin into hippocampal neurons to suppress the activity of the naturally present cofilin. This manipulation prevented both the loss of the connections between neurons and the memory deficits normally associated with sleep deprivation. Havekes et al. also found that recovery sleep leads to the re-wiring of neurons in the hippocampus. Future studies are now needed to determine how the neurons are able to re-wire themselves during recovery sleep.

DOI: 10.7554/eLife.13424.002

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