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Chapter 10: Molecular Genetic Mechanisms for Long-Term ... ... From Mechanisms of Memory, second edition By J. David Sweatt, Ph.D. Chapter 10: Chromatin Remodeling in Memory Formation

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Text of 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

  • F ig

    u re

    4 Activity-Dependent Regulation of Gene Expression in

    Neurons

  • Figure 5

    BA Long-Term Potentiation

    Impaired Long-term Synaptic Plasticity in C-Rel- /- Mice

  • F ig

    u re

    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++

    P a

    x ill

    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

    TRD MeDNA

    BINDING

    PROTEIN

    Adapter

    Protein

    HDAC1

    HDAC2

    Ac Ac

    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

    TYPE FINDING 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

    TYPE FINDING 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

    TYPE FINDING REFERENCES

    Mimic Constitutively 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