Boost and Lose Your Memory With Chemistry · 03/11/2011 · 117 signaling molecules implicated in LTP induction Park et al. “Molecular network and chromosomal clustering of genes

11/4/2011

1

ACS Webinars™

We will start momentarily at 2pm ET

Download slides after webinar: http://acswebinars.org/sacktor

1Contact ACS Webinars™at [email protected]

Have Questions?

Use the Questions Box!

Or tweet us using #acswebinars



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

www.acswebinars.org

to share ideas & learn more!


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.


The Chemical Keys to Thanksgiving DinnerHarold McGee, Published Author and New York Times Columnist


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!


Boost and Lose Your Memory With Chemistry


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

5

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

7

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

8

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

9

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

10

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

11

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

12

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

13

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

14

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


Contact ACS Webinars™at [email protected]

ACS WEBINARS™November 3, 2011

Darren Griffin Todd Sacktor

11/4/2011

15

Stay Connected…

ACS Network (search for group acswebinars)

LinkedIn (search group for acswebinars)

www.twitter.com/acswebinars

www.facebook.com/acswebinars


Upcoming ACS Webinars™www.acswebinars.org


Advancing Your Career as a Woman in the Pharmaceutical/Chemistry Industry

Annabella Villalobos, Head of Neuroscience and Antibody Directed Conjugate Medicinal Chemistry.


The Chemical Keys to Thanksgiving DinnerHarold McGee, Published Author and New York Times Columnist


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!


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.

ACS Webinars™


Documents

Boost and Lose Your Memory With Chemistry · 03/11/2011 · 117 signaling molecules implicated in LTP induction Park et al. “Molecular network and chromosomal clustering of genes