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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
Tra
ce E
yeb
link
De
lay
Eye
blin
kM
orr
is W
ate
rma
zeP
ost
tra
inin
g I
nje
ctio
n
Neurogenesis in the Adult CNS
Gould et al. (1999) Nat. Neurosci. 2:260-265.
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