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

Transcription

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 Figure 1 Summary: Three Primary Issues 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

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

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

6 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

7 Figure 5 Catalysis of camp by Adenylyl Cyclases

8 Figure 6 LTP in Adenylyl Cyclase-Deficient Mice

9 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

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

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

12 Figure 10 PKMz and LTP Maintenance

13 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

14 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

15 Figure 11 AMPA Receptor Regulation During LTP

16 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

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

18 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

19 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

20 Blue Box 1 CAMKII as a Temporal Integrator

21 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

22 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

23 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