The Biochemistry of LTP Induction. From Mechanisms of Memory by J. David Sweatt, Ph.D.

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1 The Biochemistry of LTP Induction From Mechanisms of Memory by J. David Sweatt, Ph.D.

2 Chapter 9: Dendritic Spine

3 Induction, Maintenance and Expression of LTP EXPRESSION BLOCKED EPSP MAINTENANCE BLOCKED INDUCTION BLOCKED PERIOD OF DRUG TREATMENT time tetanus

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5 LTP does not equal Memory LTP INCREASED NO CHANGE DECREASED I N C R E A S E D Nociception Receptor...(66) Ryanodine Receptor-3...(67, 68) Telencephalin.....(69) S100 B....(70) NR2B Transgenic...(71, 72) Calcineurin (inhibited)...(73) Heparin-binding Growth- Associated Molecule (transgenic). (74) M E M O R Y N O C H A N G E Mas protooncogene...(75) IP 3 Kinase... (76) PKCγ* (mild effects reported)......(77, 78) ERK (6, 79) ApoE......(80) Dystrophin.....(81) Kv1.4...(82) NO Synthase...(83, 84) GluRA...(7) t-pa...(85) Trk B receptor +/-.(86) CaMKIV/Gr..(87) Phosphatase Inhibitor 1 (88) Thy-1..(89, 90) D E C R E A S E D Heparin-binding Growth- Associated Molecule (knockout)...(74) LIM Kinase (Williams syndrome).. (91) Fragile X2 protein...(92) PSD (93) 5HT1A receptor...(94) Cav2.3 Channel.....(95) PKCβ.(9) Ataxin-1.(96) L1 Adhesion Molecule..(97) Truncated TrkB receptors....(98) Kv (99) CaMKII...( ) Neurofibromatosis Type 1..(103) CREB..(104, 105) Angelman Syndrome Gene BDNF.( ) (Ubiquitin Ligase).(110) mglur1 (111) Extracellular Superoxide Dismutase NMDAR.(32, 112) (transgenic) (113) NMDAR tail mutants.(32, 112) Zif268 (114) Ac1/8 double knockout.(115) SOD1..(116) Constitutively active TrkB receptor -/-...(86) CaMKII....(29, 117) Integrin-Associated Protein..(118) CREB/ATF Family t-pa..(119) Transcription Factors (120) NT-4.(121) CaMKIV.. (122) PACAP receptor 1(mossy PKA.(123, 124) fiber LTP) (125) Inbred mouse lines- Acid-sensing ion channel..(126) CBA and DBA... (127) Mitochondrial VDAC...(128) Calbindin/ D28...(129) Ras GRF...(130)

6 LTP induction machinery Synaptic Infrastructure 3 Neurotransmitter 5 Receptor 2 K Channels 3 NMDA 1 Receptor Ca ++ 4 IP 3 Receptor 6 Persisting Signal AMPA 2 Receptor Ca ++ Channels 4

7 The Biochemistry of LTP Induction 1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function. 2. Mechanisms upstream of the NMDA receptor that control membrane depolarization. 3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally. 4. Feed-forward and feedback mechanisms that regulate the level of calcium attained. 5. Extrinsic signals that regulate the response to the calcium influx. 6. The mechanisms for the generation of the actual persisting biochemical signals.

8 The Biochemistry of LTP Induction 1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function. 2. Mechanisms upstream of the NMDA receptor that control membrane depolarization. 3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally. 4. Feed-forward and feedback mechanisms that regulate the level of calcium attained. 5. Extrinsic signals that regulate the response to the calcium influx. 6. The mechanisms for the generation of the actual persisting biochemical signals.

9 Coincidence Detection by the NMDA Receptor Synaptic Cleft Gly Cytoplasm Ca ++ Synaptic Cleft Gly Cytoplasm Ca ++ Mg ++ Ca ++ Glu Synaptic Glutamate Alone Mg ++ Glu Glutamate plus Membrane Depolarization

10 Molecule Mr (kd) Molecule Mr (kd) Molecule Mr (kd) Glutamate Receptors Phosphatases Other signaling molecules NR1 120 NR2A 180 NR2B 180 GluR mglur1a 200 Scaffolding and adaptors PSD ChapSyn110/PSD Sap GKAP/SAPAP Shank 200 Homer 28/45 Yotiao 200 AKAP NSF 83 PKA PKA catalytic subunit 40 PKA-R2β 53 PKC PKCβ 80 PKCγ 80 PKCε 90 CaM Kinase CaM Kinase II β 60 PP1 36 PP2A 36 PP2B(calcineurin) 61 PPs 50 PTPID/SHP2 72 Tyrosine Kinases Src 60 PYK2 116 MAP Kinase pathway ERK (pan ERK) 42/44 ERK1 42/44 ERK2 42 MEK1 45 MEK2 46 MKP2 43 Rsk 90 Rsk-2 90 c-raf1 74 Small G-proteins and modulators Rac1 21 Rap2 21 SynGAP 10,12,35,60 NF1 60,101 Calmodulin 15 nnos 155 PI3 Kinase 85 PLCγ 130 cpla2 110 Citron 183 Arg Cell adhesion and cytoskeletal proteins N-Cadherin 150 Desmoglein 165 β-caternin 92 LI 200 pp120cas 120 MAP2B 280 Actin 45 α-actinin Spectrin 240/280 Myosin (brain) 205 Tubulin 50 Coractin 80/85 CortBP-1 180/200 Clathryn heavy chain 180 Dynamin 100 Hsp phosph-cam Kinase 60 Husi et al. (2001) Nature Neuroscience 3:

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12 The Biochemistry of LTP Induction 1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function. 2. Mechanisms upstream of the NMDA receptor that control membrane depolarization. 3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally. 4. Feed-forward and feedback mechanisms that regulate the level of calcium attained. 5. Extrinsic signals that regulate the response to the calcium influx. 6. The mechanisms for the generation of the actual persisting biochemical signals.

13 TABLE I DIRECT MODULATORS OF THE NMDA RECEPTOR Modulator Mechanism Effect Src family tyrosine kinases (src, fyn) tyrosine phosphorylation enhancement Scaffolding proteins loss of Zn inhibition RACK1 binding inhibitory PSD-95 scaffolding modulatory PKC ser/thr phosphoryation (direct) enhancement src activation (indirect) PKA/PP1/Yotiao phosphorylation enhancement dephosphorylation inhibition Cyclin dependent kinase 5 ser/thr phosphorylation enhancement Nitric Oxide/redox sulfhydryl nitrosylation inhibition or oxidation Polyamines (e.g. spermine, spermidine) direct binding to a modulatory augmentation site Caseine kinase II ser/thr phosphorylation enhancement modulation of polyamine effects

14 Receptor Modulation of the NMDA receptor Complex formation NMDA Receptor Leptin ApoE Ephrin B PSD95 Leptin Receptor ApoE Receptor EphB Receptor PO 4 STEP Tyr PO 4 RACK PI3K/MAPK? ERK? Src/Fyn pyk2?? CDK5 CKII PKC DAG ATP camp PKA PP1 PO 4 Yotiao Ser/Thr PL C PIP X Neurotransmitter Receptor Coupled To Adenylyl Cyclase NMDA Receptor Neurotransmitter Receptor Coupled To PLC

15 The Biochemistry of LTP Induction 1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function. 2. Mechanisms upstream of the NMDA receptor that control membrane depolarization. 3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally. 4. Feed-forward and feedback mechanisms that regulate the level of calcium attained. 5. Extrinsic signals that regulate the response to the calcium influx. 6. The mechanisms for the generation of the actual persisting biochemical signals.

16 TABLE II MECHANISMS UPSTREAM OF THE NMDA RECEPTOR INVOLVED IN MEMBRANE DEPOLARIZATION Ionic Current Molecules Involved Role K Currents Mechanisms of Modulation Voltage-dependent Kv4.2 (and Kv4.3) limit bpaps ERK, PKA, CaMKII A currents limit EPSP magnitude H Currents NCN channels regulate excitability Na Currents (HCN) cyclic nucleotides (direct) AMPA Receptors GluR1, GluR2 depolarize membrane PKA, CaMKII, PKC Aka GluR-A,B Voltage-dependent Na(v)1.6, 1.1,1.2 AP propagation Na+ currents Ca Currents? likely many AP propagation PKA Cl Currents (hypothetical) PKC (decreased inactivation) GABA Receptors all GABA-A AP firing numerous receptor subunits excitability

17 Three-way Coincidence Detection CA1 Pyramidal Neuron Strong Input 1 Back propagating Action Potential 1 2 Glu 3 NMDAR ACh 2 Kv4.2

18 The Biochemistry of LTP Induction 1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function. 2. Mechanisms upstream of the NMDA receptor that control membrane depolarization. 3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally. 4. Feed-forward and feedback mechanisms that regulate the level of calcium attained. 5. Extrinsic signals that regulate the response to the calcium influx. 6. The mechanisms for the generation of the actual persisting biochemical signals.

19 TABLE III COMPONENTS OF THE SYNAPTIC INFRASTRUCTURE NECESSARY FOR NMDA RECEPTOR FUNCTION Component Targets Role Cell Adhesion Molecules Integrins src, rho, rac, ras/mapks Transmembrane signaling, Interactions with extracellular matrix, NMDAR regulation MLCK, FAK? spine morphology? Syndecan-3 fyn, NMDAR signaling from matrix heparan sulfates to the NMDA receptor N-Cadherin other Cadherins, spine morphology? cytoskeleton Pre-post adhesion? Actin Cytoskeleton/Associated Proteins Rho membrane/cytoskeleton regulate synaptic structure interactions Cdk5 NMDA receptor increase NMDA receptor function Filamin K channels K channel localization Presynaptic Processes Glutamate release synaptic glutamate NMDA receptor activation Glutamate re-uptake synaptic glutamate limiting NMDA receptor desensitization

20 TABLE III COMPONENTS OF THE SYNAPTIC INFRASTRUCTURE NECESSARY FOR NMDA RECEPTOR FUNCTION ( Continued) Component Targets Role Anchoring/Interacting proteins PSD-95 receptors, postsynaptic organization signal transduction mechs nnos, SynGAP, GKAP NMDA receptor multiple proteins effector localization, structural Rack1/fyn NMDA receptor organization direct regulation of NMDA receptor Shank/HOMER metabotropic receptors effector localization, cytoskeleton GRIP AMPA receptors, postsynaptic organization AKAP CaMKII PICK-1/PKC PKA, PP2B signal transduction kinase and phosphatase localization regulate likelihood of LTP induction

21 PSD-95 as an Anchoring Protein for NMDA Receptors NMDAR NR2 NMDAR NR2 GAP Spectrin PSD-95 n-nos GKAP PSD95 SPAR GKAP rap SynGAP ras - cortactin Shank IP 3 R Homer PLC Group I mglur CamKII IP 3 + DAG PKC PICK-1 Receptor Trafficking NSF GRIP liprin GRASP1 (GEF for ras) ras PKA PKC AKAP79 PP2B SAP97 AMPAR GluR2,GluR3 AMPAR β-ar

22 Interactions among Integrins and Intracellular Effectors Presynaptic Retrograde Signaling Kv4.2 Channel NMDA Receptor Integrins Integrins Extracellular Matrix β subunit filamin cdk5 ERK Src/fyn? ras α-actinin talin vinculin rho rac FAK MLCK?? Dynamic Regulation Postsynaptic

23 The Biochemistry of LTP Induction 1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function. 2. Mechanisms upstream of the NMDA receptor that control membrane depolarization. 3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally. 4. Feed-forward and feedback mechanisms that regulate the level of calcium attained. 5. Extrinsic signals that regulate the response to the calcium influx. 6. The mechanisms for the generation of the actual persisting biochemical signals.

24 TABLE IV CALCIUM FEEDBACK AND FEED-FORWARD MECHANISMS Molecule/Organelle Role Modulator/Regulator VDCCs augment NMDAR-dependent PKA Ca influx Ca influx due to bpaps regulate ERK activation Endoplasmic Reticulum Ca efflux from ER, limit LTP? PLC-coupled receptors (Ca ATPase/IP3R/RyR) Presynaptic Mitochondria regulate presynaptic Ca levels unknown

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26 The Biochemistry of LTP Induction 1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function. 2. Mechanisms upstream of the NMDA receptor that control membrane depolarization. 3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally. 4. Feed-forward and feedback mechanisms that regulate the level of calcium attained. 5. Extrinsic signals that regulate the response to the calcium influx. 6. The mechanisms for the generation of the actual persisting biochemical signals.

27 TABLE V EXTRINSIC SIGNALS MODULATING THE CALCIUM RESPONSE Regulatory System Molecules Involved Role The camp Gate PKA/PP1/I1/PP2B Phosphatase Inhibition Augmented Kinase Signaling The PKC/Neurogranin PLC/PKC/Neurogranin/CaM Augmenting CaMKII Activation System Augmenting Ca-sensitive Cyclase

28 Model for the camp Gate Sweatt (2001) Curr. Biol. 11:R

29 PKC Phosphorylation of Neurogranin Metabotropic Receptor Neurogranin Phospholipase C Calmodulin PKC DAG Neurogranin PO 4 + Calmodulin

30 Neurogranin The PKC/Neurogranin system and the camp Gate Metabotropic Receptors Cyclase Coupled Receptors DAG Augmented PKC camp GATE NMDAR Initial Ca++ Signal Adenylyl Cyclase Increased Ca++/CaM Augmented CaMKII Activity

31 Four-way Coincidence Detection CA1 Pyramidal Neuron Strong Input 1 Back propagating Action Potential 1 2 Glu 3 NMDAR ACh 2 Kv4.2 4 camp GATE Norepinephrine 4

32 The Biochemistry of LTP Induction 1. Mechanisms upstream of the NMDA receptor that directly regulate NMDA receptor function. 2. Mechanisms upstream of the NMDA receptor that control membrane depolarization. 3. The components of the synaptic infrastructure that are necessary for the NMDA receptor and the synaptic signal transduction machinery to function normally. 4. Feed-forward and feedback mechanisms that regulate the level of calcium attained. 5. Extrinsic signals that regulate the response to the calcium influx. 6. The mechanisms for the generation of the actual persisting biochemical signals.

33 Figure 1 Three Primary Sites Related to Mechanisms for E-LTP Cytoskeleton Changes 2 K + Channels Phosphorylation & Insertion 2 2 Release Process AMPAR 1 *PKC? *CaMKII 1?? 3 Synaptic Tag 3 Protein Synthesis? 1 *PKC NMDAR Ca ++ *PKM zeta 1 Retrograde Messenger? = Persistently Activated

34 Figure 2 A Structures of Calcium-Binding Proteins B C D

35 Structure of CAMKII A Catalytic Autoinhibitory Self-association Inhibitory T Calmodulin Binding TT B C 286 Autonomous Activity 305/306 Inhibitory Figure 3

36 Three Different Effects of Ca/CaM on CaMKII Transient CaMKII Activation CaMKII NMDA Receptor Ca ++ / CaM Thr 286 Autophosphorylation (persistently active) CaMKII CaMKII NMDAR Association (persistently active) Figure 4

37 Domain Structures of Isoforms of PKC Regulatory Domain Catalytic Domain Classical a alpha bi/bii Beta g Gamma Novel PS Phospholipid Calcium ATP Substrate Autophosphorylation sites d Delta e Epsilon h Eta q Theta m Mu Atypical l/i Lambda/Iota z Zeta Hinge Region Figure 7

38 ites of Cleavage of Phospholipids by Phospholipases OH OH O PLD R = O OH (PO 4 ) Inositol (Inositol Phosphates) PLC O = P O R OH OH (PO 4 ) COOH C C C O R = O C C Serine PLA1 O O PLA2 NH 2 R = O C C NH 2 Ethanolamine C = O C = O + R = O C C N(CH 3 ) 3 Choline FA 1 = Any of a number of carbon fatty acids FA 2 = Typically Arachidonic Acid in plasma membrane COOH FA1 FA2 Arachidonic Acid Blue Box 3

39 Hippocampal LTP in PKC Isoform-Specific Knockout Mice A. PKC Beta Knockout B. PKC Gamma Knockout C. PKC Alpha Knockout Figure 8

40 Oxidative Activation of PKC in LTP Presynaptic Presynaptic? PKC Release Process NMDA Receptor Ca ++ Other Sources? O 2 - (Superoxide) ONOO - peroxynitrite Zn ++ release Ca++/CaM NOS NO cys{ }cys PKC Postsynaptic O 2 - Persistently Active PKC Blue Box 2

41 PKMz mrna Formation from Internal Promoter within PKCz Gene Figure 9

42 Figure 10 PKMz and LTP Maintenance

43 TABLE I: PROPOSED MECHANISMS FOR GENERATING PERSISTING SIGNALS IN E-LTP MOLECULE MECHANISM ROLE CaMKII Self-perpetuating autophosphorylation Effector phosphorylation, coupled with low phosphatase activity Structural changes Various PKCs Direct, irreversible covalent modification by reactive oxygen species Effector phosphorylation PKMz De novo synthesis of a constitutively Effector phosphorylation active kinase

44 TABLE II: PROPOSED MECHANISMS FOR AUGMENTING AMPA RECEPTOR FUNCTION IN E-LTP Mechanism Likely molecular basis Increased single-channel conductance Direct phosphorylation of AMPA receptor alpha subunits by CaMKII or PKC Increased steady-state levels of AMPAR CaMKII (+ PKC?) phosphorylation of AMPARassociated trafficking and scaffolding proteins Insertion of AMPAR into silent synapses CaMKII phosphorylation of GluR1-associated trafficking proteins

45 Glutamate Receptor Insertion and Stabilization in E-LTP NMDAR Membrane insertion NMDAR Stabilization? src PSD-95 NMDAR CaMKII* actinin 4.1 AMPAR SAP97 Stabilization AMPAR AMPAR Membrane insertion CaMKII PKC* Ca ++ trigger for E-LTP CaMKII* * = Autophosphorylated CaMKII, Autonomous PKC Figure 12

46 Retrograde Signaling in E-LTP CaM NMDA Receptor? release Ca ++ *PKC NOS PKC oxidation ONOO - O 2 - NO - O 2 -? Figure 13

47 Figure 1 Three Primary Sites Related to Mechanisms for E-LTP Cytoskeleton Changes 2 K + Channels Phosphorylation & Insertion 2 2 Release Process AMPAR 1 *PKC? *CaMKII 1?? 3 Synaptic Tag 3 Protein Synthesis? 1 *PKC NMDAR Ca ++ *PKM zeta 1 Retrograde Messenger? = Persistently Activated

48 Activity-Dependent Regulation of Local Protein Synthesis and Spine Morphological Changes in LTP AKT mtor RSK2 Ribosomal S6 Protein ERK 4E Binding Protein GSK3B NMDA Receptor mnk1 eif4e/eif2b & other eif's mrna cap binding FMRP (lost in FXMR) mglur PKC Translation Initiation Polyribosome complex mrna Targeting Change in Spine Structure Morphological Changes CaMKII? PKM zeta PSD-95 associated proteins (SAPAP4) MAP1B (1 target of FMRP) 1 & 2 alterations in dendritic protein synthesis Arc Figure 14

49 Synaptic Tagging and the E-LTP/ L-LTP Transition New gene products or proteins New gene products or proteins Synaptic tag NMDAR Signal to nucleus Synaptic Potentiation Locally generated tag captures new gene product Blue Box 4

50 The Biochemistry of LTP Induction From Mechanisms of Memory by J. David Sweatt, Ph.D.

51 From Sheng and Kim

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56 Fig. 1. RIM1 and the priming of synaptic vesicle fusion. (a) After docking, synaptic vesicles (SV) are tethered at the active zone by binding of Rab3 to the N-terminal (N) of RIM1 (Rab3-interactive molecule-1). Munc-13 is recruited to the active zone by activity of phospholipase C (PLC) and the second messenger diacylglycerol (DAG). Munc-18 binding to syntaxin (Syntx) keeps syntaxin in a `closed' conformation that cannot bind SNAP-25 (synapstosome-associated protein-25). (b) Activation of secondmessenger pathways such as those involving Ca2+, adenylate cyclase (AC), camp and protein kinase A (PKA) during induction of short-term plasticity leads to a switch in the binding partners of RIM1. Munc-13-1 binds to N-terminal RIM1, competitively inhibiting the binding of Rab3 to RIM1. Thus, a new tethering mechanism holds the SVs at the active zone, as synaptotagmin1/2 (Synat) binds to the C-terminal RIM domains in a Ca2+-dependent manner. Binding of munc-13 to syntaxin removes munc-18 and converts syntaxin's structure to an open conformation. (c) Proximity of synaptotagmin to the plasma membrane, conversion of syntaxin by Munc-13-1 to an open conformation that can interact with SNAP-25, and further increase in cytoplasmic free Ca2+ levels, promote the formation of the synaptobrevin (Syb) syntaxin SNAP-25 complex that is required for fusion.

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58 Three Pools of F-Actin in Synaptic Spines The upper panels are single computed slices through electron tomographic volumes of spines labeled for F- actin using phaloidin-eosin photo conversion, from hippocampus CA1 (A) and cerebellar cortex molecular layer (B) (see Capani et al., 2001 ). Labeling is concentrated between the lamellae of the spine apparatus (SA) and the postsynaptic density (arrowheads). Bundles of actin are seen traversing between these entities (large arrow). In Purkinje cells, which have no spine apparatus, actin filaments fill the head and also can be followed between the smooth ER and the postsynaptic membrane (large arrow). Diffuse staining for actin is also seen (asterisks). The stereo computer graphic reconstruction in the bottom panel is of the CA1 synapse and shows actin bundles (blue) as well as the spine apparatus (yellow) and the postsynaptic density (purple). These figures were kindly provided by Dr. Mark Ellisman.

59 Figure 1. LIMK Influences Postsynaptic and Presynaptic Function through Modulation of Actin Filaments Dendritic spines are made up of a head, neck, and postsynaptic density (PSD). Within the PSD, scaffold proteins such as Homer, PSD-95, and Shank, as well as others not described here, link the actin cytoskeleton to postsynaptic receptors including AMPA and NMDA glutamate receptors. Results in this issue of Neuron by Meng et al. (2002 ) demonstrate that LIMK-1 is partially responsible for proper dendritic morphology and long-term potentiation (LTP), presumably via its effect on actin filament dynamics, through phosphorylation and inactivation of ADF/cofilin (AC). In LIMK-1 / mice, the morphology of dendritic spines is altered. The spines have a thicker neck and smaller postsynaptic density length and smaller spine area. Results presented by Meng et al. (2002 ) also reveal that the LIMK-1 / mice have enhanced basal release of presynaptic vesicles and an enhanced synaptic depression, suggesting a role for LIMK-1 (and most likely actin dynamics) in neurotransmitter release. Figure by Patrick D. Sarmiere and James R. Bamburg

60 Chapter 9: Biochemical Mechanisms for Information Storage at the Cellular Level From Mechanisms of Memory, second edition By J. David Sweatt, Ph.D.

61 Figure 11 AMPA Receptor Regulation During LTP

62 Figure 5 Catalysis of camp by Adenylyl Cyclases

63 Figure 6 LTP in Adenylyl Cyclase-Deficient Mice

64 Altered Protein Synthesis as Trigger for Memory Memory-Causing Event NMDA Receptor Dendritic Spine Housekeeping Proteins Constitutive Effector Protein Signal to Specific Proteins Altered Synthesis of Specific Proteins = The Trigger mrna Effector Protein Complex = The Readout* Perpetuated Structural/ Functional Change Constitutive Protein Synthesis Induced Protein Synthesis MEMORY STORAGE *New Spine Structure, Potentiated Synapse,etc. Positive Feedback to Synthesis or Recruitment = The Maintenance Mechanism

65 Blue Box 1 CAMKII as a Temporal Integrator

66 From Sheng and Kim