Biochemical Mechanisms for Long-term Information

Storage at the Cellular Level

From Mechanisms of Memory by J. David Sweatt, Ph.D.

Protein Synthesis Dependence of L-LTP

Kang et al. (2001) Cell 106:771-783.

THE CASE FOR GENE EXPRESSION IN L-LTP

EXPERIMENT TYPE and FINDING

Block

Block of L-LTP with protein synthesis inhibitors Block of L-LTP with RNA synthesis inhibitors 

Loss of L-LTP with CREB KOsBlock of L-LTP with Arc antisense 

Loss of L-LTP with CaMKIV KO Loss of L-LTP with zif268 KO  

THE CASE FOR GENE EXPRESSION IN L-LTP

EXPERIMENT TYPE and FINDING

MeasureIncreased zif268/krox24 mRNA Increased krox20 Increased expression of fos, jun IEG mRNAs 

Increased CREB phosphorylation 

Increased CRE read-outIncreased elk-1 phosphorylation Increased Arc/Arg3.1 mRNA expression 

Increased AMPA receptor protein Increased BDNF message Increased tissue Plasminogen Activator message Increased C/EBP beta (in long-term memory) 

Increased HOMER 

Increased MAP Kinase Phosphatase-1 Increased SSAT message Increased MAP2 message  

MimicConstitutively active CREB augments L-LTP induction

CREB Binding Protein (CBP)

cAMP Response Element5’-TGACGTCA-3’

TATA Sequence

CREB CREB

Basal Transcription Factor IID (TFIID)

Complex

ser 133 ser 133

RNA Helicase A

RNAPolymerase II

Histone

pKAF

acetylation

TargetGene

PO4 PO4

The CREB/CRE Gene Regulation System

Figure courtesy of Jennifer GatchelBrookhaven National Protein Structure Data Bank, Rendered with Rasmol

Crystal Structure of CREB bound to the CRE

CBPCBPp300p300

OO

OOPPOO

OO

Histone acetylation

Elk-1Elk-1 OO

OOPPOO

OO

CREBCREB OO

OOPPOO

OOCBPCBPp300p300

OO

OOPPOO

OO c-fosfosB junBegr-1etc...

Histone Acetyltransferase (HAT) – Regulation of Gene Expression

MKP-3/Dual Specificity PhosphataseUpstream Regulatory Elements

C/EBP Elk-1

MZF1

Octamer-bindingfactor 1

NF-B

CHOP-C/EBP

ras-REBP

MyT1

c-Rel

E2F

Wilm'sTumorSuppressor

EVI-1Factor

E2F

MAZ

MKP-3

GCBox

92 total regulatory elements

CBF/NFY

Components of the LTP Gene Expression System

1. A core signal transduction cascade linking calcium to the transcription factor CREB

2. Modulatory influences that impinge upon this cascade3. Additional transcription factors besides CREB that may be involved

in L-LTP induction4. Gene targets in L-LTP5. mRNA targeting and transport6. Effects of the gene products on synaptic structure

Components of the LTP Gene Expression System

1. A core signal transduction cascade linking calcium to the transcription factor CREB

2. Modulatory influences that impinge upon this cascade3. Additional transcription factors besides CREB that may be involved

in L-LTP induction4. Gene targets in L-LTP5. mRNA targeting and transport6. Effects of the gene products on synaptic structure

G Protein

ERK1/2

MEK1/2

Raf1

R1GrbSOS

RasPKC

R2

B-Raf

PKA

R3

Rap

AC

Gene Expression

CRE

CREB

P

CBP

RSK2

GEF

NF1GAP

NO.

Ca2+

Ca2+

Nucleus

AChR

Components of the LTP Gene Expression System

1. A core signal transduction cascade linking calcium to the transcription factor CREB

2. Modulatory influences that impinge upon this cascade3. Additional transcription factors besides CREB that may be involved

in L-LTP induction4. Gene targets in L-LTP5. mRNA targeting and transport6. Effects of the gene products on synaptic structure

Activity-dependent Regulation of Gene Expression

Components of the LTP Gene Expression System

1. A core signal transduction cascade linking calcium to the transcription factor CREB

2. Modulatory influences that impinge upon this cascade3. Additional transcription factors besides CREB that may be involved

in L-LTP induction4. Gene targets in L-LTP5. mRNA targeting and transport6. Effects of the gene products on synaptic structure

CRE SRE zif268

C/EBP krox20

AMPARHOMERBDNFNT-3

MKP-1SSAT

Arc

CBP/CREB

CaMKIV + ERK

Elk-1

RSK2

Transcriptional Regulation Pathways

Components of the LTP Gene Expression System

1. A core signal transduction cascade linking calcium to the transcription factor CREB

2. Modulatory influences that impinge upon this cascade3. Additional transcription factors besides CREB that may be involved

in L-LTP induction4. Gene targets in L-LTP5. mRNA targeting and transport6. Effects of the gene products on synaptic structure

Steward and Worley (2001) PNAS 98:7062-7068.

Activity-dependent Arc Expression and Dendritic Localization

Components of the LTP Gene Expression System

1. A core signal transduction cascade linking calcium to the transcription factor CREB

2. Modulatory influences that impinge upon this cascade3. Additional transcription factors besides CREB that may be involved

in L-LTP induction4. Gene targets in L-LTP5. mRNA targeting and transport6. Effects of the gene products on synaptic structure

Hypothetical Mechanisms for Activity-dependent changes in Synaptic Structure

Presynaptic

Postsynaptic

IntegrinsIntegrins

Ca++Ca++

actin

Pax

illin

FAK (Focal Adhesion Kinase)

grb2/sos cas/crk src

ERK JNK

α αββrho rac

Dynamiccytoskeletalregulation

Cadherins

Catenins

?

DMPK

MyosinPhosphatase

CytoskeletalMyosin II

-

-

α-actinintalin

vincu

lin α-actinin

Signaling Mechanisms Used by Integrins and Cadherins

Components of the LTP Gene Expression System

1. A core signal transduction cascade linking calcium to the transcription factor CREB

2. Modulatory influences that impinge upon this cascade3. Additional transcription factors besides CREB that may be involved

in L-LTP induction4. Gene targets in L-LTP5. mRNA targeting and transport6. Effects of the gene products on synaptic structure

Villarreal et al. (2002). Nat. Neurosci. 5:48-52.

L-LTP Decay is an Active Process

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Neurogenesis in the Adult CNS

Gould et al. (1999) Nat. Neurosci. 2:260-265.