Despite the fact that humans spend a large part of their lives engaged in sleep, we still
do not know why. This question may be one of the most profound problems still facing
Sleep likely serves multiple important functions, but it is certain that it is critical
to support higher cognitive processes such as learning and memory. The informational
capacity of a human brain is vast, but the daily ability to incorporate new information
may be finite. The restorative functions of sleep renew our capacity to incorporate new
information, while at the same time allowing for the consolidation of long-term memory,
incorporating our daily learning with our previous experiences.
In addition to asking why we sleep, we might also ask what actually changes in our brains
while asleep? Because we know that it benefits learning and memory, at least one major
target of sleep will likely be neuronal synapses, the sites of memory formation and
maintenance. In work performed over recent years, I and my colleagues have attempted to
gain a comprehensive picture of how synapses were altered during sleep and have begun
the process of elucidating the molecular mechanisms driving these changes.
Synapses in the brain can change in both strength and number in a process called synaptic
plasticity. Long-term potentiation and long-term depression (LTP and LTD, respectively)
are widely believed to form the basis of learning and memory.
Neurons can also express a form of synaptic plasticity called homeostatic scaling,
whereby a neuron simultaneously strengthens (scaling-up) or weakens (scaling-down) all
of its synapses in a uniform direction. Since the first observation of this phenomenon
was made by Gina Turrigiano in 1998 (1), homeostatic scaling has been almost entirely
investigated in vitro. During this time, many of the underlying molecular mechanisms
have been described. However, one critical question remains: When do neurons in a living
animal actually use homeostatic scaling?
A controversial model of how sleep alters the brain to benefit cognition has emerged
called the “sleep homeostasis hypothesis” (SHY), championed by Chiara
Cirelli and Giulio Tononi. SHY posits that synapses are strengthened when we are awake
because they are encoding our daily experiences, predominantly through LTP. This is
offset during sleep by a global weakening of synapses that restores synaptic strength to
basal states (2). Meanwhile, some
memories are consolidated, whereas others are erased.
I believe that homeostatic scaling-down in cultured neurons is the best model we have for
understanding the global weakening of synapses during sleep. Therefore, to understand
how sleep modifies synapses, I dissected the brains of mice that were awake or had been
sleeping and then used biochemical fractionation to isolate the postsynaptic density
(PSD), a fraction highly enriched with synaptic material.
My first question was how many of the changes that had been previously observed during
homeostatic scaling-down could also be seen in synapses from a sleeping mouse? The
similarities were remarkable. In particular, sleep and scaling-down involved a reduction
in synaptic levels of AMPA-type glutamate receptors, major excitatory transmitter
receptors in the brain (3). This
finding is consistent with SHY, strongly suggesting that synapses across the brain
become weaker during sleep.
To gain a more comprehensive picture of how synapses were modified during sleep, we used
quantitative proteomics to examine the PSD samples. Our results indicated that a full
20% of the synapse proteome was altered in the samples taken from sleeping mice, as
compared with samples taken from mice that were awake, showing that profound changes
were occurring at synapses throughout the brain during sleep.
This data set gave us a “parts list” of molecules regulated by sleep that
is already helping us determine the molecular mechanisms that drive sleep-dependent
remodeling of synapses.
In cultured neurons, one of the clusters of signaling molecules that was removed from
synapses during sleep is regulated by a protein called Homer1a, which is expressed when
neurons become highly active and initiates the homeostatic scaling-down response.
Interestingly, the Homer1a protein was targeted to synapses in mice during sleep (3).
In further experiments, I determined that the targeting of Homer1a to synapses was highly
sensitive to chemicals in the brain that mediate arousal and sleepiness (3). Noradrenaline, for example,
which is strongly associated with an alert awake brain, prevented Homer1a from entering
the synapse. Adenosine, which builds up in our brains while we are awake and causes
sleepiness as it accumulates, promoted the targeting of Homer1a to synapses. These
findings led me to believe that Homer1a serves as an integrator of arousal and sleep
I therefore hypothesize that when we are fully aroused and awake, the brain’s
ability to strengthen synapses and encode information from our experiences is maximized
as noradrenaline blocks Homer1a access to synapses and prevents scaling-down. After a
long day, synapses have become stronger and we begin to grow tired. Adenosine
accumulated in our brains during this period will promote Homer1a targeting to synapses
to initiate scaling-down and synapse weakening. An important element of this model is
that Homer1a protein is expected to be expressed at higher levels in neurons that were
the most active and engaged in learning during the waking state, and these neurons will
be the ones that benefit the most from the restorative process of scaling-down while
When faced with a challenging intellectual problem, ancient wisdom tells us to
“sleep on it”; all will become clearer in the morning. It may be that
there is a bit of molecular truth to this old adage. With continuing work, we can gain
further insights into why we sleep and how sleep actually works to enable cognitive
functions such as learning and memory.
FINALIST Graham H. Diering
Graham Diering received his bachelor’s and doctorate degrees at the University
of British Columbia. As a postdoc at Johns Hopkins University, he characterized
changes in synapse composition that occur during sleep. He is now an assistant
professor at the University of North Carolina, Chapel Hill; his laboratory focuses
on the role of sleep in neural development. www.sciencemag.org/content/358/6362/457.2