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11/4/2011
1
ACS Webinars™
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Download slides after webinar: http://acswebinars.org/sacktor
11/4/2011
2
Do you use ACS Webinars in the classroom?
We’d like to hear from you!
Email us ([email protected]) or go to
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to share ideas & learn more!
3Contact ACS Webinars™at [email protected]
Upcoming ACS Webinars™www.acswebinars.org
Thursday, November 10, 2011
Advancing Your Career as a Woman in the Pharmaceutical/Chemistry Industry
Annabella Villalobos, Head of Neuroscience and Antibody Directed Conjugate Medicinal Chemistry.
Thursday, November 17, 2011
The Chemical Keys to Thanksgiving DinnerHarold McGee, Published Author and New York Times Columnist
4Contact ACS Webinars™at [email protected]
Annabella Villalobos
Harold McGee
11/4/2011
3
ex·treme[ik-streem] adjective, -trem·er, -trem·est, noun
adjective1.of a character or kind farthest removed from the ordinary or average: extreme measures.2.utmost or exceedingly great in degree: extreme joy.3.farthest from the center or middle; outermost; endmost: the extreme limits of a town.4.farthest, utmost, or very far in any direction: an object at the extreme point of vision.
Now you can look forward to more ACS ‘Extreme Chemistry’ Webinars™ featuring
Darren Griffin!
5Contact ACS Webinars™at [email protected]
Boost and Lose Your Memory With Chemistry
Download slides after webinar: http://acswebinars.org/sacktor
Contact ACS Webinars™at [email protected]
ACS WEBINARS™November 3, 2011
Darren Griffin Todd Sacktor
11/4/2011
4
Boost and Lose Your Memory with Chemistry
Todd C. Sacktor, M.D.
Distinguished Professor of Physiology, Pharmacology, and Neurology
The Robert F. Furchgott Center for Behavioral and Neural Science
SUNY Downstate Medical Center
Acquisition
Consolidation
Retrieval
Time
Mem
ory
Short-term(STM)
Long-term (LTM)
‘Storage’
‘Reconsolidation’
What is the machinery that keeps memory going?
Phases of memory
11/4/2011
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Amaral, DG & Witter,MP, Neuroscience 31:571 (1989)
Bliss, TV and Lømo, T, J Physiol 232:331 (1973)
What is the machinery that keeps LTP going?
11/4/2011
6
Sanes and Lichtman“Can molecules explain long-term potentiation?”Nature Neuroscience 2:597 (1999)
117 signaling molecules implicated in LTP induction
Park et al.“Molecular network and chromosomal clustering of genes involved in synaptic plasticity in the hippocampus”JBC 281:30,195 (2006)
1684 genes out of 12,000 (14%) change expression levels after LTP
11/4/2011
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DAG Ca2+
DAG
conventional
novel
atypical
PKM
N C
regulatory domain catalytic domain
pseudosubstrate
pseudosubstrate
pseudosubstrate
Ab
PKC gene family
���
conventional novel atypical
200 –
93 –
69 –
46 –
kDa
Western blot of rat hippocampal extract
skeletal muscle
Naik et al., Distribution of protein kinase Mand the complete protein kinase C isoform family in rat brain.J Comp Neuro 426:243 (2000)
11/4/2011
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Sacktor, TC, How does PKM maintain long-term memory?Nature Reviews Neuroscience, in press
PKM inhibition reverses perforant path-dentate granule cell LTP in vivo
Pastalkova et al., Storage ofspatial information by the maintenance mechanism of LTP.Science, 313:1141 (2006).
11/4/2011
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Hippocampus-dependent active place avoidance
Pastalkova et al., Storage ofspatial information by the maintenance mechanism of LTP.Science, 313:1141 (2006).
QuickTime™ and aYUV420 codec decompressor
are needed to see this picture.
11/4/2011
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Spatial training increases PKM in the hippocampus and sensory cortex of mice, 24 hours after training
control trained
The Experimental System: Conditioned Taste Aversion (CTA)
0
50
100
Ave
rsio
n I
nd
ex
LiCl ip
Saline ip
(Same magnitude of memoryeven if first test performed
after several months)
Central gustatory area, insular cortex
11/4/2011
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ZIP erases 3 month-old memory
Day 1 Day 2
CTA CTA3 months
ZIP
Day 95 Day 97 Day 98 Day 99
Test 1 Test 2 Test 3Protocol:
* p<0.01Test 1 Test 2 Test 3
100
20
60
Ave
rsio
n i
nd
ex
ZIP
Control*
**
Shema, et al., Boundary conditions for the maintenanceof memory by PKM in neocortex. Learn. Mem.: 16:122-128 (2009).
CMV
PKMzeta IRESIRES GFP
From the inhibitor (ZIP) back to the enzyme (PKM): PKM overexpression in the insular cortex
Shema, et al., Enhancement of consolidated long-term memory by overexpression of PKM in the neocortex. Science, 331:1207 (2011).
11/4/2011
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Dominant negative PKM disrupts and active PKM enhances established memories
Shema, et al., Enhancement of consolidated long-term memory by overexpression of PKM in the neocortex. Science, 331:1207(2011).
PKM decreases with Adeposition in 5XFamilial AD Aoverexpressing mouse
Shao, C., unpublished
11/4/2011
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Neurological and Psychiatric Disorders in which PKM has been implicated
— central neuropathic pain (anterior cingulate, insular cortex, spinal cord)
— AD, aggregates (limbic system: hippocampus, entorhinal cortex, amygdala)
— post-traumatic stress disorder (insular cortex)
— morphine, cocaine addiction (VTA, nucleus accumbens)
— focal dystonia, phantom limb (striatum, sensorimotor cortex)?
Conclusions
—memories can be erased by inhibiting PKM.
— memories can be enhanced by increasing PKM activity,
either during memory formation or after they have already been established.
— PKM is thus the first identified component of the molecular mechanism of long-term memory storage. Pharmacologically manipulating PKM, through greater understanding of its binding partners, may lead to control over our memory.
11/4/2011
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Sacktor lab (past and present)N. BlaceJ. CraccoJ. CraryA.I. HernandezS. HrabetovaX. JiangJ. JothianandanM. KellyJ. LibienM. NaikP. OstenP. SerranoR. SondhiE. SubletteA. TcherepanovD. TianL. ValsamisY. Yao
PKM whole-cell perfusionD. LingL. Benardo (Downstate)
PKM and synaptic taggingS. SajikumarS. NavakkodeJ.U. Frey (Leibniz Institute, Magdeburg)
PKM mRNA dendritic targetingI. MuslimovC. NimmrichH. Tiedge (Downstate)
Spatial behavior and in vivo LTPAndre FentonE. Pastalkova (Downstate)
DrosophilaE. DrierJ. Yin (U. Wisconsin)
Fear conditioningE. FriedmanJ. Yin (U. Wisconsin)A. Kelly (U. Wisconsin)S. Maren (U. Michigan)
Conditioned taste aversionR. ShemaY. Dudai (Weizmann Inst.)
Sensorimotor memoryJ. FrancisL von Kraus(Downstate)
Alzheimers DiseaseC. ShaoW. OxberryS. Mirra (Downstate)
Supported by:Sacktor: NIH NIMHRO1 MH53576RO1 MH57068
Dudai/Sacktor:US-IsraelBinational Science Foundation
Boost and Lose Your Memory With Chemistry
Download slides after webinar: http://acswebinars.org/sacktor
Contact ACS Webinars™at [email protected]
ACS WEBINARS™November 3, 2011
Darren Griffin Todd Sacktor
11/4/2011
15
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29Contact ACS Webinars™at [email protected]
Upcoming ACS Webinars™www.acswebinars.org
Thursday, November 10, 2011
Advancing Your Career as a Woman in the Pharmaceutical/Chemistry Industry
Annabella Villalobos, Head of Neuroscience and Antibody Directed Conjugate Medicinal Chemistry.
Thursday, November 17, 2011
The Chemical Keys to Thanksgiving DinnerHarold McGee, Published Author and New York Times Columnist
30Contact ACS Webinars™at [email protected]
Annabella Villalobos
Harold McGee
11/4/2011
16
Do you use ACS Webinars in the classroom?
We’d like to hear from you!
Email us ([email protected]) or go to
www.acswebinars.org
to share ideas & learn more!
31Contact ACS Webinars™at [email protected]
ACS Webinars™ does not endorse any products or services. The views
expressed in this presentation are those of the presenter and do not necessarily
reflect the views or policies of the American Chemical Society.
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