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 Basal Transcription Factor IID (TFIID) Complex ser 133 RNA Helicase A RNA Polymerase II Histone pKAF acetylation Target Gene PO 4 CREB/CRE Gene Regulation System

Figure 3 Crystal Structure of CREB Bound to the CRE

Figure 4 Activity-Dependent Regulation of Gene Expression in Neurons

Figure 5 BA Long-Term Potentiation Impaired Long-term Synaptic Plasticity in C-Rel - /- Mice

Figure 6 CRESRE 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 Ca ++ actin Paxillin FAK (Focal Adhesion Kinase) grb2/sos cas/crk src ERKJNK αα ββ rhorac Dynamic cytoskeletal regulation Cadherins Catenins ? DMPK Myosin Phosphatase Cytoskeletal Myosin II - - α-actinin talin vinculin α-actinin Signaling Mechanisms Utilized by Integrins and Cadherins

Figure 10 Memory and the Cellular Level

Figure 11 B A 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 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 FINDINGREFERENCES 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 FINDINGREFERENCES 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 FINDINGREFERENCES Mimic Constitutively active CREB augments L-LTP induction (14) TABLE I – THE CASE FOR GENE EXPRESSION IN L-LTP CONTINUED

DISEASEGENEFUNCTIONEPIGENETIC EFFECT Rubinstein- Taybi Syndrome CBPHistone acetyltransferase ↑ histone acetylation Rett SyndromeMECP2Binds 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 diseaseAPPAPP intracellular domain acts as a Notch-like transcription factor; associated with the HAT TIP60 ↓ histone acetylation SchizophreniareelinAn 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