Chapter 11: Inherited Disorders of Human Memory Mental Retardation Syndromes. From Mechanisms of Memory, second edition By J. David Sweatt, Ph.D.
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1 Chapter 11: Inherited Disorders of Human Memory Mental Retardation Syndromes From Mechanisms of Memory, second edition By J. David Sweatt, Ph.D.
2 Chapter 11: Mental Retardation Syndromes
3 Table I: Mouse Models of Human Mental Retardation Syndromes Human Mental Retardation Syndromes Gene Product Potential Targets Mouse Model Learning Defects? LTP Change? References Neurofibromatosis Neurofibromin 1 (NF1) ras/ ERK + + Costa et al (4, 39) adenylyl cyclase Tong et al (9) cytoskeleton Coffin-Lowry Ribosomal S6 Kinase2 CREB +? Dufresne et al (12) Syndrome (rsk2) ribosomal S6 protein Harum et al (13) Angelman Syndrome iquitin Ligase (E6AP) p53 tumor suppressor + + Jiang et al (40) protein, others?
4 Table I: Mouse Models of Human Mental Retardation Syndromes Continued Fragile X Mental FMR1 Protein (RNA protein synthesis +? Retardation 1 binding proteins) machinery, (strain mrna targeting, spine structure, LTD dependen t) Bardoni et al (17) Fragile X Mental FMR2 protein Unknown Gu et al (41) Retardation 2 (putative transcription Gene Expression factor) Rett Syndrome Methyl-CpG Binding Transcriptional?? Shahbazian et al (23) Protein 2 (MeCP 2 ) repressors--regulation of unknown genes Myotonic Dystrophy Dystrophin Protein Na + channels,?? Mistry et al (42) Kinase (DMPK) Tau, many others
5 Table I: Mouse Models of Human Mental Retardation Syndromes Cont. Myotonic Dystrophy Dystrophin Protein Na + channels,?? Mistry et al (42) Kinase (DMPK) Tau, many others Down Syndrome DS critical locus Multiple genes including + + Siarey et al (36) (Trisomy 21) DYRK1A and SOD DYRK1A (minibrain unknown +? Altafaj et al (35) kinase homolog) Superoxide Dismutase Superoxide dependent + + Gahtan et al (43) (SOD) processes--redox regulation of PKC, ras, transcription factors Williams Syndrome WS critical locus: cytoskeleton + + Morris et al (44) LIMK-1 Elastin Syntaxin 1A FKBP6 EIFH4 extracellular matrix spine morphology
6 Figure 1 Signaling Pathways Implicated in Human Memory Formation
7 Signal Transduction Pathways Involved in Learning and Memory Ca 2+ R 1 GEF NO. Neurofibromatosis MR Grb SOS Ras NF1 GAP Raf1 PKC R 2 MEK1/2 ERK1/2 B-Raf R 4 Rap Ca 2+ PKA Coffin-Lowry Syndrome RSK2 AC R 3 G Protein NF1 Mnk1/2 eif4e Protein Synthesis MAPs Spine Structure Rubinstein-Taybi Syndrome P CBP CREB CRE Nucleus Fragile X Syndrome Gene Expression Figure 2
8 Figure 3 Ras-Dependent spacial learning deficits in NF1 K-ras N-ras Farnesyl Transferase Inhibitor
9 Figure 4 Ras-Dependent LTP deficits in NF1
10 iquitination Pathway of Proteins E1 Charging E1 E1 Step 1 ATP E1 Step 2 E2 Charging E2 E3 Transfer Step 4 E2 Ligase E3 E2 Target Protein Complex Formation Step 3 E3 Ligase Target Poly- iquitination Step 5 Target Protein Figure 5
11 Figure 6 Selective Deficit in Context-Dependent Fear Conditioning in e3a Maternal Deficient Mice
12 Impairment of Hippocampal LTP in e3a Maternal Deficient mice Figure 7
13 Fragile X Mental Retardation Syndrome Gene Structure Current Model of Fragile X Mental Retardation Coding Region Regulatory Region FMR1 Gene CGG Expansion in Regulatory Region Point Mutation in Coding Region Disruption Of FMR1 Gene Loss of FMR1 Protein (FMRP) FMRP = 63K RNA binding protein that binds to poly (G) and poly (U) structures FMRP Structure FMR1/FXR Interaction domain KH KH Domain Domain Ribosome Interaction Domain RGG Box Figure 8 RGG Box = Arginine & Glycine-rich domain KH domain = Ribonucleoprotein K homology domain
14 Figure 9 DHPG Induces Greater LTD of Synaptic Responses in Hippocampus
15 Figure 10 Role of mglur5 in Fragile X Mental Retardation
16 Slope fepsp (Standardized to Baseline) Enhanced LTP in FMR2 Knockout Mice A Wildtype Mutant Time (min) Figure 11
17 Williams Syndrome rac rho PAK, ROCK PKC LIMK-1 (Williams Syndrome) Direct phosphorylation (inhibitory) Actin Depolymerization Factor (ADF) / cofilin ADF / Cofilin promotes Actin depolymerization Actin Cytoskeleton Loss of LIMK-1 causes increased actin turnover Altered Dendritic Spine Blue Box 3 Augmented LTP, Learning Impairments
18 Non-Syndromic X-Linked Mental Retardation Dbl (Diffuse B-cell Lymphoma) Rho GEF6 Rho GAP Rho GDI + _ Rho PAK3 (p21 Activated Kinase) JNK p38 LTD disruption? raf-1 Cytoskeleton Blue Box 4
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