Sleep-Dependent Oscillation of Glutamatergic Synaptic Phenotype in the Motor Cortex

Core Concepts

Sleep-wake cycles drive an oscillation in the glutamatergic synaptic phenotype of motor cortex pyramidal neurons, with waking increasing synaptic strength and decreasing synaptic plasticity potential, and sleep reversing these changes.

Abstract

The content examines the impact of sleep and sleep deprivation on the glutamatergic synaptic properties of layer 2/3 pyramidal neurons in the motor cortex. Key findings include: Sleep deprivation (SD) increases the AMPA/NMDA ratio of evoked excitatory postsynaptic currents (EPSCs) in these neurons, indicating a shift towards stronger AMPAR-mediated synaptic transmission. This effect is reversed by recovery sleep. SD also decreases the fraction of "silent synapses" (containing NMDARs but not AMPARs), suggesting a reduction in the availability of synapses that can undergo long-term potentiation (LTP). This silent synapse reduction is again reversed by recovery sleep. Single-nucleus RNA sequencing reveals that the SD transcriptional response is most pronounced in excitatory, intratelencephalically-projecting (ExIT) pyramidal neurons. These DEGs are enriched for synaptic shaping component (SSC) genes and autism spectrum disorder (ASD) risk genes. The sleep-dependent transcriptional changes are regulated by the transcription factor MEF2C and its repressor HDAC4, which oscillate in activity and nuclear localization in response to sleep need. The authors propose that the sleep-wake oscillation of glutamatergic synaptic phenotype, mediated by MEF2C/HDAC4 regulation of sleep genes, provides a framework for optimal motor learning and training, balancing synaptic strengthening during waking with synaptic renormalization and plasticity potential during sleep.

Stats

Sleep deprivation significantly increases the AMPA/NMDA EPSC ratio in layer 2/3 motor cortex pyramidal neurons compared to control sleep and recovery sleep conditions. The ratio of AMPAR failure rate to NMDAR failure rate is significantly decreased by sleep deprivation, indicating a reduction in the fraction of silent synapses, which is reversed by recovery sleep.

Quotes

"Sleep loss increases AMPA-synaptic strength and number in the neocortex. However, this is only part of the synaptic sleep loss response." "Silent synapses are absent, decreasing the plastic potential to convert silent NMDA to active AMPA synapses. These sleep loss changes are recovered by sleep."

Key Insights Distilled From

Sleep need driven oscillation of glutamate synaptic phenotype

by Vogt,K., Kul... at www.biorxiv.org 02-06-2024

https://www.biorxiv.org/content/10.1101/2024.02.05.578985v4

Deeper Inquiries

How might the sleep-dependent oscillation of glutamatergic synaptic phenotype impact the learning and consolidation of complex motor skills?

The sleep-dependent oscillation of glutamatergic synaptic phenotype plays a crucial role in the learning and consolidation of complex motor skills. During waking periods, there is an increase in glutamatergic synaptic strength and number, leading to a bias towards synaptic strengthening. This bias can limit the potential for potentiating plasticity, as the available slots for AMPA receptors saturate. However, during sleep, there is a recovery of the glutamatergic synaptic phenotype, with a decrease in AMPA/NMDA ratio and an increase in silent synapses. This shift towards decreased synaptic strength and increased potential for plasticity sets the stage for optimal learning and consolidation of motor skills. The oscillation from a state of increased synaptic strength at the end of the active phase to a state of decreased strength at the start of the active phase allows for a recursive incremental learning process. This process ensures that there is a balance between strengthening synapses during wakefulness and promoting plasticity during sleep. By biasing glutamatergic synapses towards decreased strength and increased potential for long-term potentiation at the beginning of the active phase, the brain can effectively explore and learn new motor tasks in a multi-dimensional learning space.

How might the sleep-dependent oscillation of glutamatergic synaptic phenotype impact the learning and consolidation of complex motor skills?

The association between sleep disruption and autism spectrum disorder (ASD) symptoms can be attributed to various neural circuit and behavioral changes. One significant factor is the overlap in gene expression patterns between sleep-responsive genes and ASD risk genes. The sleep-dependent oscillation of glutamatergic synaptic phenotype, particularly in excitatory pyramidal neurons projecting intra-telencephalically, can contribute to alterations in neural circuits that are implicated in ASD. Additionally, disruptions in sleep patterns can lead to changes in neurotransmitter systems, such as adenosine and glutamate, which play a role in regulating arousal and synaptic activity. These disruptions can impact the balance between excitatory and inhibitory neurotransmission, leading to alterations in neural circuit function and behavior. Furthermore, sleep disturbances can affect neurodevelopmental processes critical for the establishment of proper neural circuits, which are often disrupted in individuals with ASD. Overall, the complex interplay between sleep disruption, alterations in neural circuits, and changes in neurotransmitter systems can contribute to the manifestation of ASD symptoms in individuals with sleep disturbances.

Could pharmacological or optogenetic manipulation of the MEF2C-HDAC4 pathway be a potential therapeutic strategy for disorders of sleep and motor function?

Pharmacological or optogenetic manipulation of the MEF2C-HDAC4 pathway holds promise as a potential therapeutic strategy for disorders of sleep and motor function. The MEF2C transcription factor plays a crucial role in regulating the expression of sleep genes and controlling synaptic plasticity. HDAC4, as a repressor of MEF2C, modulates the transcriptional activity of MEF2C in response to changes in sleep need. By targeting the MEF2C-HDAC4 pathway, it may be possible to modulate the expression of genes involved in sleep regulation and synaptic plasticity. This could help restore the balance of glutamatergic synaptic strength and plasticity, promoting optimal learning and motor function. Additionally, manipulating this pathway could potentially address disruptions in neural circuits associated with sleep disorders and motor deficits. Pharmacological interventions targeting MEF2C or HDAC4 activity, or optogenetic techniques to modulate the activity of specific neuronal populations involved in this pathway, could offer novel therapeutic approaches for conditions characterized by sleep disturbances and motor dysfunction. Further research into the precise mechanisms and effects of such interventions is needed to fully explore their therapeutic potential.