Chapter 10: Molecular Genetic Mechanisms for Long-Term ......From Mechanisms of Memory, second...

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