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Alteration in Cortical mEPSCs Depending on Sleep/ Wake Evidence for Synaptic Remodeling in Sleep CSB445: Kathleen Harrison

Synaptic homeostasis hypothesis synaptic depression during sleep

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Alteration in Cortical mEPSCs Depending on Sleep/ Wake

Evidence for Synaptic Remodeling in Sleep

CSB445: Kathleen Harrison

The problem

Evidence to support wake being associated to synaptic potentiation and sleep with depression.

Great interest in this hypothesis: however, there are still areas of support lacking direct proof for changes in synaptic alteration.

>1600 Papers

>1000 Citations

600 Citations

On sleep and the synapse after 2003

On Tononi & Cirelli’s 2003 paper

45 PapersOn sleep and the synapse before 2003

On Tononi & Cirelli’s 2006 paper

Remember:

(Wong, Y. 2015)

“(1) Wakefulness is associated with synaptic potentiation in cortical circuits; (2) Synaptic potentiation is tied to the homeostatic regulation of NREM sleep EEG slow wave activity;

(3) Slow wave activity is associated with synaptic downscaling;

(4) Synaptic downscaling is tied to the beneficial effects of sleep on neural function and, indirectly, on performance’’

(Tononi & Cirelli, 2003)

Why?

>25% Calories used in the brainBut only ~2% of mass4.7 x 109 ATP/ neuron/ second

Support for the Model

Neuronal

(Vyazovskiy et al., 2008)

Structural Electrical Synaptic

40% AMPAr post wake/ sleep

Molecular

(Bushey, Tononi, Cirelli. 2011)

# & density post wake/ sleep firing rates post wake/ sleep evoked AP post wake/ sleep

(Vyazovskiy et al., 2008)

(Vyazovskiy et al., 2009)

Hypothesis:

● Miniature EPSCs (mEPSCs) from frontal cortex slices of mice and rats

● Awake or asleep should show changes in frequency and amplitude of mEPSCs

● Increased after waking and decreased after sleep, independent of time of day

● Sleep Deprivation and recovery sleep should increase, and decrease mEPSCs respectively

Looking for Change: Pre/Post Synapse

Vesical (Quanta) Release FrequencyAMPAr Trafficking & Scaffold remodeling

Experiments

Sleep VS WakeCortex harvested when awake, or asleep - mSPSCs

Sleep Deprived Cortex harvested at same time, but one group awake,

Sleep RecoveryCortex harvested at same time, but one group given recovery

Sleep in Other ModelsCortex harvested from mice after sleep deprivation

The Technology Patch Clamp

How it works

Step 1

Isolate

Cortex => Neuron

Step 2

Voltage Clamp

Whole cell clamp

Step 3

Record & Analyze

mESPCs: Hz & pA

Experiments

Sleep VS WakeCortex harvested when awake, or asleep - mSPSCs

Sleep Deprived Cortex harvested at same time, but one group awake,

Sleep RecoveryCortex harvested at same time, but one group given recovery

Sleep in Other ModelsCortex harvested from mice after sleep deprivation

Experiments

Sleep VS WakeCortex harvested when awake, or asleep - mSPSCs

Result:Presynaptic - Higher frequency of NT release Postsynaptic - Increase in amplitude

(Liu et al. 2010)

Experiments

Result:Presynaptic - Higher frequency of NT release Postsynaptic - Increase in amplitude

Sleep Deprived Cortex harvested at same time, but one group awake,

(Liu et al. 2010)

Experiments

Result:Presynaptic - Decreased frequency of NT release Postsynaptic - Decrease in amplitude

Sleep RecoveryCortex harvested at same time, but one group given recovery

(Liu et al. 2010)

Experiments

Result:Presynaptic - Increased frequency of NT release Postsynaptic - Increase in amplitude

Sleep in Other ModelsCortex harvested from mice after sleep deprivation

(Liu et al. 2010)

Conclusion:

● Found that Hz and pA of mEPSCs increased after waking, decreased after sleep● Independent of time of day● Recovery sleep decreased mEPSCs Hz and pA● Suggest sleep facilitates synaptic depotentiation

“Stronger synapses require more energy, space, and supplies: generalized renormalization of synapses may be an important function of sleep.”

(Liu et al. 2010)

Pros

● Contradictory results when scaled?● Importance of checking data!

Cons

● Good Evidence for SHY

● Good area of investigation

● Strengths of hypothesis

Variation in mEPSP post SD

mEPSP post SD same as wake/ control?

References:Bushey, Tononi, Cirelli. (2011) Sleep and Synaptic Homeostasis: Structural Evidence in Drosophila

Liu ZW, Faraguna U, Cirelli C, Tononi G, Gao XB. (2010) Direct Evidence for Wake-Related Increases and Sleep-Related Decreases in Synaptic Strength in Rodent Cortex

VyazovskiyVV, CirelliC,Pfister-GenskowM,FaragunaU,TononiG (2008) Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep.

Vyazovskiy VV, Olcese U, Lazimy YM, Faraguna U, Esser SK, Williams JC, Cirelli C, Tononi G (2009) Cortical firing and sleep homeostasis.

Questions?