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From Mechanisms of Memory , second edition By J. David Sweatt, Ph.D.

Chapter 9: Biochemical Mechanisms for Information Storage at the Cellular Level. From Mechanisms of Memory , second edition By J. David Sweatt, Ph.D. Chapter 9: Dendritic Spine. Summary: Three Primary Issues Related to Mechanisms for E-LTP. Cytoskeleton Changes. 2. K + Channels.

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From Mechanisms of Memory , second edition By J. David Sweatt, Ph.D.

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

  2. Chapter 9: Dendritic Spine

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

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

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

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

  7. Catalysis of cAMP by Adenylyl Cyclases Figure 5

  8. LTP in Adenylyl Cyclase-Deficient Mice Figure 6

  9. Regulatory Domain Catalytic Domain Classical PS Phospholipid Calcium ATP Substrate a alpha bI/bII Beta g Gamma Auto-phosphorylation sites •• •• •• Novel d Delta e Epsilon h Eta q Theta m Mu Atypical l/i Lambda/Iota z Zeta Hinge Region Domain Structures of Isoforms of PKC Figure 7

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

  11. PKM mRNA Formation from Internal Promoter within PKC Gene Figure 9

  12. PKM and LTP Maintenance Figure 10

  13. AMPA Receptor Regulation During LTP Figure 11

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

  15. GAP43 NMDA Receptor ↑CaM ? ↑release Ca++ *PKC NOS NO- ? PKC oxidation ONOO- O2- O2- Retrograde Signaling in E-LTP Figure 13

  16. Activity-Dependent Regulation of Local Protein Synthesis and Spine Morphological Changes in LTP Figure 14

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

  18. CAMKII as a Temporal Integrator Blue Box 1

  19. Presynaptic? Presynaptic PKC Release Process NMDA Receptor Other Sources ONOO- peroxynitrite Ca++ ? O2- (Superoxide) Zn++ release cys{ }cys Ca++/CaM NOS PKC NO· Persistently Active PKC O2- Postsynaptic Oxidative Activation of PKC in LTP Blue Box 2

  20. Sites of Cleavage of Phospholipids by Phospholipases Blue Box 3

  21. 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 Synaptic Tagging and the E-LTP/ L-LTP Transition Blue Box 4

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