Download “Astrocytic Modulation of Sleep Homeostasis and Cognitive

“Astrocytic Modulation of Sleep
Homeostasis and Cognitive
Consequences of Sleep Loss”
Michael M. Halassa, Cedrick Florian, Tommaso Fellin, James R. Munoz, SoYoung Lee, Ted Abel, Philip G. Haydon, and Marcos G. Frank
Journal Club, 10-February-2009
Glia
• Glia:Neurons = 10:1
• Traditionally 3 types of
Glia
– Astrocytes
– Oligodendrocytes
– Microglia
– Recently NG2+ Cells Added
• “Brain Glue”!?
©2009 McGraw-Hill Companies, From
“http://www.rienstraclinic.com/newsletter/2006/2006Jul.html”
• Functions
Astrocytes!
• Defined By GFAP (Glial
Fibrillary Acidic Protein)
Expression
• Highly Ramified,
Intracellular Coupling
• Functions:
–
–
–
–
Metabolic Roles
K+ Buffering
Blood Brain Barrier
Precursor Cells?
©2007 The University of Utah, Genetic Science Learning Center
• Occupy defined, nonoverlapping domains
– Hippocampus
• >100,000 Synapses
• Bushong et al., 2002
– Cortex
• 2-8 Somata
• 300-600 Dendrites
• Halassa et al, 2007
Bushong EA, Martone ME, Jones YZ, Ellisman MH Protoplasmic astrocytes in CA1
stratum radiatum occupy separate anatomical domains. J Neurosci 22; 183-92, 2002
Figure 2. One astrocyte enwraps several neuronal somata
Halassa, M. M. et al. J. Neurosci. 2007;27:6473-6477
Copyright ©2007 Society for Neuroscience
The Tripartite Synapse
• Filipodia and Lamellipodia
– Envelop Synapse
• Clearance of
Neurotransmitters
• Receptors
• Calcium Transients
• Gliotransmission
…And Now
THE PAPER
Outline
• GFAP Driven dnSNARE
– Attenuate exocytotic Gliotransmission
• Assessed effects on Sleep and EEG
• Pharmacological experiments to characterise cause of
these effects
• Object recognition task to examine effects on sleep
deprivation induced memory impairments
dnSNARE
• Tetracycline
Transactivator (tTA) under
GFAP promoter
• dnSNARE under tet.O
promoter
• tTA activates tet.O and
drives expression of
dnSNARE
• Conditional supression:
– Doxycycline in the diet
• <50% cortical astrocytes
express transgene
• No significant alterations to
total sleep time, REM time,
NREM time, or 24-hour EEG
spectra between groups
– Open Circles/Bars: Wild Type
– Closed Circles/Bars: dnSNARE
During the Light Phase…
(C-G, After 6-Hour Sleep Deprivation Protocol)
• Mechanism assumed to be
inhibition of extracellular
adenosine build-up, acting
via A1R
• Tests:
– Occlusion: (G)
– Mimic: (H) and (I)
Effects of Sleep Deprivation on
Memory
• Sleep deprivation, linked to impaired memory and
cognitive function
• Novel Object Recognition task sensitive to the effects of
“sleep pressure”
• dnSNARE/A1R antagonism
protects against Sleep
deprivation induced
impairments
• dnSNARE Rats
– No difference in exploration
time
– No differences in Anxiety
– No Motor impairment
– No contextual fear conditioning
impairments
• Not an Effect of Sleep, rather
Sleep Pressure/Adenosine