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Chapter 10:
Molecular Genetic Mechanisms
for Long-Term Information
Storage at the Cellular Level
From Mechanisms of Memory, second edition
By J. David Sweatt, Ph.D.
Chapter 10: Chromatin Remodeling in Memory Formation
Figure 1
Protein Synthesis Dependence of L-LTP
Figure 2
CREB Binding Protein (CBP)
cAMP Response Element
5’-TGACGTCA-3’TATA Sequence
CREB CREB
Basal Transcription
Factor IID (TFIID)
Complex
ser 133 ser 133
RNA Helicase A
RNA
Polymerase II
Histone
pKAF
acetylation
Target
Gene
PO4 PO4
CREB/CRE Gene Regulation System
Figure 3
Crystal Structure of CREB Bound to the CRE
Fig
ure
4Activity-Dependent Regulation of Gene Expression in
Neurons
Figure 5
BA Long-Term Potentiation
Impaired Long-term Synaptic Plasticity in C-Rel- /- Mice
Fig
ure
6
CRE SRE zif268
C/EBP krox20
AMPAR
HOMER
BDNF
NT-3
MKP-1
SSAT
Arc
CBP/CREB
CaMKIV + ERK
Elk-1
RSK2
Transcriptional Regulation Pathways Controlling
Expression of Synaptic Plasticity-Associated Genes
Figure 7
Activity-Dependent ARC Expression and Dendritic
Localization
Figure 8
Hypothetical Mechanisms and Activity-Dependent
Changes in Synaptic Structure
Figure 9
Presynaptic
Postsynaptic
Integrins
Integrins
Ca++Ca++
Pa
xill
in
FAK (Focal Adhesion Kinase)
grb2/sos cas/crk src
ERK JNK
α α
ββrho rac
Dynamic
cytoskeletal
regulation
Cadherins
Catenins
?
DMPK
Myosin
Phosphatase
Cytoskeletal
Myosin II
-
-
α-actinin
α-actinin
Signaling Mechanisms Utilized by Integrins and Cadherins
Figure 10
Memory and the Cellular Level
Figure 11
BA
Methylation of Cytosine Side-Chains in DNA
Figure 12
“CpG Island” in the BDNF Gene
Figure 13
MBD
TRDMeDNA
BINDING
PROTEIN
Adapter
Protein
HDAC1
HDAC2
AcAc
DNA Methylation-Dependent Gene Silencing
Figure 14
Homology Model of MBD of MECP2 Interacting with
CpG within DNA Duplex
Figure 15
Nucleosome Interaction with DNA
Figure 16
The Histone Code
Histone
Acetyltransferase
(HAT)
Histone
Deacetylase
(HDAC)
Figure 17
Bidirectional Regulation of Histone Acetylation by HAT’s
and HDAC’s
Figure 18
Epigenetics in Contextual Fear Memory --- Histone Code
Figure 19
Neurogenesis in the Adult Human Hippocampus
TABLE I – THE CASE FOR GENE EXPRESSION IN L-
LTP
EXPERIMENT
TYPEFINDING REFERENCES
Block Block of L-LTP with protein synthesis inhibitors (76)
Block of L-LTP with RNA synthesis inhibitors (1, 2, 77)
Loss of L-LTP with CREB KOs (3-5)
Block of L-LTP with Arc antisense (13)
Loss of L-LTP with CaMKIV KO (7, 8, 78)
Loss of L-LTP with zif268 KO (6)
Loss of L-LTP with c-rel KO (21)
EXPERIMENT
TYPEFINDING REFERENCES
Measure Increased zif268 / krox24 mRNA (40)
Increased krox20 (44)
Increased expression of fos, jun IEG mRNAs (40, 42, 43)
Increased CREB phosphorylation (24, 34, 35)
Increased CRE read-out (12, 79)
Increased elk-1 phosphorylation (35)
Increased Arc/Arg3.1 mRNA expression (13, 54, 59)
Increased AMPA receptor protein (51)
Increased BDNF message (46, 80)
Increased tissue Plasminogen Activator message (47)
Increased C/EBP beta (in long-term memory) (45)
Increased HOMER (11, 53, 72)
Increased MAP Kinase Phosphatase-1 (35, 50)
Increased SSAT message (49)
Increased MAP2 message (81)
TABLE I – THE CASE FOR GENE EXPRESSION IN L-LTP
CONTINUED
EXPERIMENT
TYPEFINDING REFERENCES
MimicConstitutively active CREB augments L-LTP
induction (14)
TABLE I – THE CASE FOR GENE EXPRESSION IN L-LTP
CONTINUED
DISEASE GENE FUNCTION EPIGENETIC EFFECT
Rubinstein-
Taybi Syndrome
CBP Histone
acetyltransferase
↑ histone acetylation
Rett Syndrome MECP2 Binds to CpG
dinucleotides and recruits
HDACs
↓ histone acetylation
Fragile X mental
retardation
FMR1 and FMR2* Expansion of CGG or
CCG repeats results in
aberrant DNA methylation
around FMR1 and FMR2
genes
↑ DNA methylation
↑ histone acetylation
Alzheimer’s disease APP APP intracellular domain
acts as a Notch-like
transcription factor;
associated with the HAT
TIP60
↓ histone acetylation
Schizophrenia reelin An extracellular matrix
protein, involved in
synapse development
↑ DNA methylation
around the reelin gene
*Trinucleotide expansions in FMR1 and FMR2. APP, amyloid precursor protein; CBP, cyclic-
AMP response-element-binding protein; FMR, fragile X mental retardation; HAT, histone
acetyltransferases; HDAC, histone deacetylase; MECP2, methyl CpG-binding protein 2; TIP60, HIV-1 Tat
interactive protein, 60kDa.
TABLE II – EPIGENETICS IN HUMAN COGNITIVE
DISORDERS
Blue Box 1
Neural Development and Differentiation
Mother’s Day --- Everyday of Your Life
Blue Box 2