1 / 38

The Biochemistry of LTP Induction

The Biochemistry of LTP Induction. From Mechanisms of Memory by J. David Sweatt, Ph.D. From Sheng and Kim. LTP induction machinery. Neurotransmitter Receptor. Synaptic Infrastructure. 5. 3. 2. K Channels. 3. 4. IP 3 Receptor. Ca ++. NMDA Receptor. 1. Persisting Signal. 6.

reese
Download Presentation

The Biochemistry of LTP Induction

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. From Sheng and Kim

  3. LTP induction machinery Neurotransmitter Receptor Synaptic Infrastructure 5 3 2 K Channels 3 4 IP3 Receptor Ca++ NMDA Receptor 1 Persisting Signal 6 2 Ca++ Channels AMPA Receptor 4

  4. The Biochemistry of LTP Induction 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.

  5. Husi et al. (2001) Nature Neuroscience 3: 661-669.

  6. The Biochemistry of LTP Induction 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.

  7. TABLE I – DIRECT MODULATORS OF THE NMDA RECEPTOR

  8. Receptor Modulation of the NMDA receptor Leptin ApoE Ephrin B NMDA Receptor Leptin Receptor ApoE Receptor EphB Receptor PSD95 Tyr RACK PI3K/MAPK PO4 PO4 ? STEP ? ERK Complex formation ? Src/Fyn pyk2 CDK5 CKII ? DAG PKC PP1 PKA PO4 ATP cAMP Yotiao PLC Ser/Thr PIPX Neurotransmitter Receptor Coupled To Acetyl Choline Neurotransmitter Receptor Coupled To PLC NMDA Receptor

  9. The Biochemistry of LTP Induction 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.

  10. TABLE II – MECHANISMS UPSTREAM OF THE NMDA RECEPTOR INVOLVED IN MEMBRANE DEPOLARIZATION

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

  12. The Biochemistry of LTP Induction 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 III – COMPONENTS OF THE SYNAPTIC INFRASTRUCTURE NECESSARY FOR NMDA RECEPTOR FUNCTION

  14. TABLE III – COMPONENTS OF THE SYNAPTIC INFRASTRUCTURE NECESSARY FOR NMDA RECEPTOR FUNCTION ( Continued)

  15. PSD-95 as an Anchoring Protein for NMDA Receptors NMDAR NR2 NMDAR NR2 GAP PSD95 PSD-95 n-NOS GKAP Spectrin GKAP SPAR Shank SynGAP Homer actin cortactin rap - IP3R Group I mGluR actin ras PLC IP3 + DAG CamKII PKA PKC Receptor Trafficking PKC liprin ras AKAP79 PP2B NSF SAP97 GRASP1 (GEF for ras) PICK-1 GRIP β-AR AMPAR GluR2,GluR3 AMPAR

  16. From Sheng and Kim

  17. 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 second-messenger 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.

  18. 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.

  19. Figure 1. LIMK Influences Postsynaptic and Presynaptic Function through Modulation of Actin FilamentsDendritic 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

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

  21. The Biochemistry of LTP Induction 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.

  22. TABLE IV – CALCIUM FEEDBACK AND FEED-FORWARD MECHANISMS

  23. The Biochemistry of LTP Induction 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 V – EXTRINSIC SIGNALS MODULATING THE CALCIUM RESPONSE

  25. Model for the cAMP Gate Sweatt (2001) Curr. Biol. 11:R391-394.

  26. PKC Phosphorylation of Neurogranin Metabotropic Receptor Neurogranin Phospholipase C Calmodulin DAG PKC Neurogranin PO4 + Calmodulin

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

  28. The Biochemistry of LTP Induction 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.

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

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

More Related