The role of sleep in regulating structural plasticity and synaptic strength: Implications for memory and cognitive function

Summary

Dendritic spines are the major sites of synaptic transmission in the central nervous system. Alterations in the strength of synaptic connections directly affect the neuronal communication, which is crucial for brain function as well as the processing and storage of information. Sleep and sleep loss bidirectionally alter structural plasticity, by affecting spine numbers and morphology, which ultimately can affect the functional output of the brain in terms of alertness, cognition, and mood. Experimental data from studies in rodents suggest that sleep deprivation may impact structural plasticity in different ways. One of the current views, referred to as the synaptic homeostasis hypothesis, suggests that wake promotes synaptic potentiation whereas sleep facilitates synaptic downscaling. On the other hand, several studies have now shown that sleep deprivation can reduce spine density and attenuate synaptic efficacy in the hippocampus. These data are the basis for the view that sleep promotes hippocampal structural plasticity critical for memory formation. Altogether, the impact of sleep and sleep loss may vary between regions of the brain. A better understanding of the role that sleep plays in regulating structural plasticity may ultimately lead to novel therapeutic approaches for brain disorders that are accompanied by sleep disturbances and sleep loss.

Introduction

It is estimated that the human brain consists of approximately 86 billion neurons and every single neuron can be connected with thousands of other neurons [1], suggesting that there are close to 100 trillion of these neuronal connections or synapses. Synapses are the locus where information is transferred from a pre-to a postsynaptic neuron [2], which is largely mediated by neurotransmitters that are released by the presynaptic axon terminals and then bind to receptors on the postsynaptic dendritic spines. The strength of these neuronal connections (i.e., synaptic strength) can be measured in several ways. In case of glutamatergic neurons, which are the focus of this review, one can measure the amount of calcium influx in the postsynaptic glutamatergic cell, postsynaptic glutamatergic receptor currents, and the expression levels of glutamate receptors. Synaptic strength can be regulated and altered, a property often referred to as synaptic plasticity or structural plasticity with the latter emphasizing changes in synaptic morphology [3], [4]. This capacity to change the strength of synaptic connections directly affects the communication between neurons, which ultimately is of crucial importance for brain function at large, in terms of reactivity to external stimuli as well as the processing and storage of information [5], [6], [7].

Dendritic spines are specialized postsynaptic membranous compartments that protrude from the dendritic shaft [8], [9] and were first identified by Santiago Ramón y Cajal at the end of the 19th century [10]. Transmission electron microscopy allowed the visualization of spines in greater detail and revealed that dendritic spines are indeed specialized compartments which contain neurotransmitter receptors, postsynaptic densities (PSD) and several other organelles [11]. In recent years, a more detailed view of the spine ultrastructure was obtained with the aid of advanced imaging techniques [11], [12], [13], which has been pivotal for our developing understanding of synaptic plasticity and the way this influences synaptic function and efficacy [14]. Synaptic plasticity and regulation of synaptic strength includes the formation of new spines, spine elimination, and modifications in spine morphology [15]. It can also involve changes in neurotransmitter receptor content and thereby alter the responsiveness to neurotransmitter input [8]. Given the fundamental importance of synaptic plasticity in regulating neuronal function and communication, it is of no surprise that disruptions in synaptic plasticity and aberrant spine morphology can be observed in a variety of neuropsychiatric and neurocognitive disorders [2], [16] including those that are characterized by disturbed sleep [17].

It has become increasingly clear that alterations in spine dynamics and synaptic efficacy are modulated by sleep and sleep loss, which ultimately may affect important brain functions such as alertness, information processing, cognitive function and mood [18], [19]. Indeed, even a single brief period of several hours of sleep deprivation already has a profound impact on memory [20]. Work in the last few decades has started to elucidate some of the molecular mechanisms by which sleep and sleep loss directly modulate structural plasticity in the brain and how these changes relate to memory processes including those that require the hippocampus.

Here, we review the current state of knowledge regarding the causal role of sleep in influencing spine dynamics. Subsequently, we describe recent work providing insight into the molecular mechanisms by which sleep deprivation perturbs structural and synaptic plasticity with emphasis on the hippocampus. In the final section of this review, we relate these current insights on how sleep loss affects structural plasticity and ultimately causes memory deficits, to the general hypothesis on how sleep and sleep loss impact the brain according to the synaptic homeostasis hypothesis.