Maintaining wakefulness is associated with a progressive increase in the need for sleep. This phenomenon has been linked to changes in synaptic function. The synaptic adhesion molecule Neuroligin-1 (NLG1) controls the activity and synaptic localization of N-methyl-Daspartate receptors, which activity is impaired by prolonged wakefulness. We here highlight that this pathway may underlie both the adverse effects of sleep loss on cognition and the subsequent changes in cortical synchrony. We found that the expression of specific Nlg1 transcript variants is changed by sleep deprivation in three mouse strains. These observations were associated with strainspecific changes in synaptic NLG1 protein content. Importantly, we showed that Nlg1 knockout mice are not able to sustain wakefulness and spend more time in nonrapid eye movement sleep than wild-type mice. These changes occurred with modifications in waking quality as exemplified by low theta/alpha activity during wakefulness and poor preference for social novelty, as well as altered delta synchrony during sleep. Finally, we identified a transcriptional pathway that could underlie the sleep/wake-dependent changes in Nlg1 expression and that involves clock transcription factors. We thus suggest that NLG1 is an element that contributes to the coupling of neuronal activity to sleep/wake regulation.ChIP | EEG | gene expression | sleep homeostasis | synaptic plasticity S leep is crucial for learning, memory, and other functions essential for proper functioning of the brain and body (1, 2). These functions have been associated with the sleep recovery process, which defines a level of pressure for sleep that increases with wakefulness and dissipates during sleep and that is reflected by changes in sleep intensity (3, 4). Sleep intensity is indexed by electroencephalographic (EEG) markers of neuronal synchrony in delta frequencies (1-4 Hz) measured during nonrapid eye movement (NREM) sleep (5). During wakefulness, mechanisms favoring desynchrony in the delta range predominate, and the brain can maintain cognition, whereas during sleep, events promoting network synchrony mostly take place with high delta activity thought to be permissive of recovery (3, 6). The sleep recovery process has been hypothesized to originate and contribute to the maintenance of both synaptic and network equilibrium (6-8). This notion is supported by the observation that specific plasticityrelated genes may be directly involved in regulating sleep need (9). Certain clock genes may also directly contribute, in a circadian-independent manner, to the sleep recovery process (5, 9). However, the mechanisms underlying the capacity and requirement of the brain to switch from an alert desynchronized state to an unconscious synchronized state remain elusive.Glutamate, the main excitatory neurotransmitter of the brain, can induce long-term modifications of synaptic transmission and, thus, changes in network connectivity. This is achieved mainly via glutamate's action on two types of receptors: N-methyl-D-aspa...

Sleep is critical for normal brain function and mental health. However, the molecular mechanisms mediating the impact of sleep loss on both cognition and the sleep electroencephalogram remain mostly unknown. Acute sleep loss impacts brain gene expression broadly. These data contributed to current hypotheses regarding the role for sleep in metabolism, synaptic plasticity and neuroprotection. These changes in gene expression likely underlie increased sleep intensity following sleep deprivation (SD). Here we tested the hypothesis that epigenetic mechanisms coordinate the gene expression response driven by SD. We found that SD altered the cortical genome-wide distribution of two major epigenetic marks: DNA methylation and hydroxymethylation. DNA methylation differences were enriched in gene pathways involved in neuritogenesis and synaptic plasticity, whereas large changes (>4000 sites) in hydroxymethylation where observed in genes linked to cytoskeleton, signaling and neurotransmission, which closely matches SD-dependent changes in the transcriptome. Moreover, this epigenetic remodeling applied to elements previously linked to sleep need (for example, Arc and Egr1) and synaptic partners of Neuroligin-1 (Nlgn1; for example, Dlg4, Nrxn1 and Nlgn3), which we recently identified as a regulator of sleep intensity following SD. We show here that Nlgn1 mutant mice display an enhanced slow-wave slope during non-rapid eye movement sleep following SD but this mutation does not affect SD-dependent changes in gene expression, suggesting that the Nlgn pathway acts downstream to mechanisms triggering gene expression changes in SD. These data reveal that acute SD reprograms the epigenetic landscape, providing a unique molecular route by which sleep can impact brain function and health.

Our results suggest that EphA4 is involved in circadian sleep regulation.