biochemical mechanisms for long-term information storage at the cellular level from mechanisms of...
TRANSCRIPT
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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.
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Protein Synthesis Dependence of L-LTP
Kang et al. (2001) Cell 106:771-783.
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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
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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
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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
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Figure courtesy of Jennifer GatchelBrookhaven National Protein Structure Data Bank, Rendered with Rasmol
Crystal Structure of CREB bound to the CRE
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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
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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
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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
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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
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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
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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
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Activity-dependent Regulation of Gene Expression
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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
![Page 16: Biochemical Mechanisms for Long-term Information Storage at the Cellular Level From Mechanisms of Memory by J. David Sweatt, Ph.D](https://reader035.vdocuments.us/reader035/viewer/2022070403/56649f315503460f94c4c403/html5/thumbnails/16.jpg)
CRE SRE zif268
C/EBP krox20
AMPARHOMERBDNFNT-3
MKP-1SSAT
Arc
CBP/CREB
CaMKIV + ERK
Elk-1
RSK2
Transcriptional Regulation Pathways
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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
![Page 18: Biochemical Mechanisms for Long-term Information Storage at the Cellular Level From Mechanisms of Memory by J. David Sweatt, Ph.D](https://reader035.vdocuments.us/reader035/viewer/2022070403/56649f315503460f94c4c403/html5/thumbnails/18.jpg)
Steward and Worley (2001) PNAS 98:7062-7068.
Activity-dependent Arc Expression and Dendritic Localization
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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
![Page 20: Biochemical Mechanisms for Long-term Information Storage at the Cellular Level From Mechanisms of Memory by J. David Sweatt, Ph.D](https://reader035.vdocuments.us/reader035/viewer/2022070403/56649f315503460f94c4c403/html5/thumbnails/20.jpg)
Hypothetical Mechanisms for Activity-dependent changes in Synaptic Structure
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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
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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
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Villarreal et al. (2002). Nat. Neurosci. 5:48-52.
L-LTP Decay is an Active Process
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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.