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

Chapter 9: Dendritic Spine

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

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

Figure 3 TTT CatalyticAutoinhibitorySelf-association Inhibitory Calmodulin Binding 286 Autonomous Activity 305/306 Inhibitory A BC Structure of CAMKII

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

Figure 5 Catalysis of cAMP by Adenylyl Cyclases

Figure 6 LTP in Adenylyl Cyclase-Deficient Mice

Figure 7 Regulatory DomainCatalytic Domain  Delta  Epsilon  Eta  Theta  Mu Novel  Lambda/Iota  Zeta Atypical  alpha  Beta  Gamma Classical CalciumATPSubstratePhospholipidPS Hinge Region Auto- phosphorylation sites Domain Structures of Isoforms of PKC

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

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

Figure 10 PKM  and LTP Maintenance

TABLE I: PROPOSED MECHANISMS FOR GENERATING PERSISTING SIGNALS IN E-LTP MOLECULEMECHANISMROLE CaMKIISelf-perpetuating autophosphorylationEffector phosphorylation, coupled with low phosphatase activityStructural changes Various PKCs Direct, irreversible covalent modification by reactive oxygen speciesEffector phosphorylation PKM  De novo synthesis of a constitutivelyEffector phosphorylation active kinase

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

Figure 11 AMPA Receptor Regulation During LTP

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

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

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

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

Blue Box 1 CAMKII as a Temporal Integrator

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

Blue Box 3 Sites of Cleavage of Phospholipids by Phospholipases

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