Inherited Disorders of Human Memory – Mental Retardation Syndromes Chapter 11: Inherited Disorders of Human Memory – Mental Retardation Syndromes From Mechanisms of Memory, second edition By J. David Sweatt, Ph.D.

Chapter 11: Mental Retardation Syndromes

Table I: Mouse Models of Human Mental Retardation Syndromes Gene Product Potential Targets Mouse Model References Learning Defects? LTP Change? 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 Ubiquitin Ligase (E6AP) p53 tumor suppressor Jiang et al (40) protein, others?

Table I: Mouse Models of Human Mental Retardation Syndromes Continued Fragile X Mental FMR1 Protein (RNA protein synthesis + ? Bardoni et al (17) Retardation 1 binding proteins) machinery, (strain   mRNA targeting, dependent) spine structure, LTD 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 (MeCP2) repressors--regulation of unknown genes Myotonic Dystrophy Dystrophin Protein Na+ channels, Mistry et al (42)  Kinase (DMPK) Tau, many others

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 extracellular matrix Elastin spine morphology Syntaxin 1A FKBP6 EIFH4

Signaling Pathways Implicated in Human Memory Formation Figure 1

Signal Transduction Pathways Involved in Learning and Memory G Protein ERK1/2 MEK1/2 Raf1 R1 Grb SOS Ras PKC R2 B-Raf PKA R3 Rap AC Gene Expression Mnk1/2 eIF4E Protein Synthesis MAPs Spine Structure CRE CREB P CBP RSK2 GEF NF1 GAP Neurofibromatosis MR NO. Ca2+ Nucleus R4 Coffin-Lowry Syndrome Rubinstein-Taybi Syndrome Fragile X Syndrome Figure 2

Ras-Dependent spacial learning deficits in NF1 K-ras N-ras Farnesyl Transferase Inhibitor Figure 3

Ras-Dependent LTP deficits in NF1 Figure 4

Complex Formation Step 3 Ubiquitination Pathway of Proteins Step 1 Step 2 Complex Formation Step 3 Step 4 Step 5 E1 Charging E2 Charging E2—E3 Transfer Target Poly-Ubiquitination Figure 5

Selective Deficit in Context-Dependent Fear Conditioning in Ube3a Maternal Deficient Mice Figure 6

Impairment of Hippocampal LTP in Ube3a Maternal Deficient mice Figure 7

Fragile X Mental Retardation Syndrome Current Model of Fragile X Mental Retardation Coding Region Regulatory Region CGG Expansion in Regulatory Region Point Mutation in Coding Region Disruption Of FMR1 Gene Loss of FMR1 Protein (FMRP) FMR1/FXR Interaction domain Ribosome Interaction Domain RGG Box KH RGG Box = Arginine & Glycine-rich domain KH domain = Ribonucleoprotein K homology domain FMRP = 63K RNA binding protein that binds to poly (G) and poly (U) structures FMR1 Gene Gene Structure FMRP Figure 8

DHPG Induces Greater LTD of Synaptic Responses in Hippocampus Brief application of the mGluR agonist DHPG (5 min; 100 μM) induces greater LTD of synaptic responses in hippocampus of Fmr1-KO mice as compared with WT littermate controls. (A1) Plotted are average (±SEM) FP slope values over the time course of the experiment. In Fmr1-KO animals, the response 60 min after treatment was depressed to 77 ± 3% of preDHPG baseline (n = 21 slices from 9 mice; open circles); in interleaved WT controls, the response was depressed to 88 ± 4% of baseline (n = 15 slices from 8 mice; filled circles; different at P = 0.02; t test). (A2) Representative FPs (2 min average) taken at the times indicated by the numbers on the graph. (Bar = 1 mV; 5 msec.) (B) Cumulative probability distributions of FP slope values (% of baseline), measured 1 h after DHPG in individual slices from both KO and WT groups. The distribution in KO mice is significantly different from that in WT mice as determined by Kolmolgarov–Smirnov test (P < 0.05). Figure 9

Role of mGluR5 in Fragile X Mental Retardation Model. Previous research has shown that activation of mGluR5 stimulates the internalization of AMPA receptors and NMDARs (not shown; ref. 11). The stable expression of this modification requires protein synthesis, which we propose is negatively regulated by FMRP synthesized in response to mGluR activation. Therefore, in the absence of FMRP, LTD magnitude is increased. Figure 10

Enhanced LTP in FMR2 Knockout Mice -20 -10 10 20 30 40 50 60 100 150 200 250 Mutant Wildtype Time (min) Slope fEPSP (Standardized to Baseline) Figure 11

Actin Cytoskeleton—Loss of LIMK-1 causes increased actin turnover Williams Syndrome rho PAK, ROCK LIMK-1 (Williams Syndrome) Actin Depolymerization Factor (ADF) / cofilin Actin Cytoskeleton—Loss of LIMK-1 causes increased actin turnover Altered Dendritic Spine Augmented LTP, Learning Impairments rac PKC Direct phosphorylation (inhibitory) ADF / Cofilin promotes Actin depolymerization Blue Box 3

Non-Syndromic X-Linked Mental Retardation Rho PAK3 (p21 Activated Kinase) JNK p38 Cytoskeleton raf-1 LTD disruption? Dbl (Diffuse B-cell Lymphoma) Rho GEF6 Rho GAP Rho GDI GEFs + _ Blue Box 4