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

Chapter 9:Biochemical Mechanisms for

Information Storage at the Cellular Level

Chapter 9: Dendritic Spine

Fig

ure

1

ReleaseProcess

*PKC

AMPAR

NMDAR

Phosphorylation& Insertion

Ca++

RetrogradeMessenger?

*CaMKII

*PKMzeta

*PKC

Synaptic Tag

K+ Channels

Protein Synthesis

?

?

* = Persistently Activated

CytoskeletonChanges

?

?

1

1

1

1

2

2

2

3

3

Summary: Three Primary Issues Related to Mechanisms for E-LTP

Fig

ure

2

A

B

C D

Structures of Calcium-Binding Proteins

Figure 3

T TT

Catalytic Autoinhibitory Self-association

Inhibitory

CalmodulinBinding

286Autonomous

Activity

305/306Inhibitory

A

B C

Structure of CAMKII

Figure 4

NMDAReceptor

CaMKII

Transient CaMKIIActivation

Thr 286Autophosphorylation(persistently active)

NMDAR Association(persistently active)

CaMKII

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 Domain Catalytic Domain

DeltaEpsilonEtaThetaMu

Novel

Lambda/Iota Zeta

Atypical

alphaBetaGamma

ClassicalCalcium ATP SubstratePhospholipidPS

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

MOLECULE MECHANISM ROLE

CaMKII Self-perpetuating autophosphorylation Effector phosphorylation,

  coupled with low phosphatase activity Structural changes

     

Various PKCsDirect, irreversible covalent modification by reactive

oxygen species Effector phosphorylation

     

PKM De novo synthesis of a constitutively Effector phosphorylation

  active kinase  

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 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

AM

PA

R

NM

DA

R

NM

DA

R

AM

PA

R

SAP974.1

actinactinin

CaMKII*

CaMKII

Ca++ triggerfor E-LTP

NM

DA

R

AM

PA

R

src

CaMKII*PKC*

PSD-95

* = Autophosphorylated CaMKII, Autonomous PKC

Stabilization Stabilization

?Membraneinsertion

Membraneinsertion

Glutamate Receptor Insertion and Stabilization in E-LTP

Figure 13

NMDAReceptor

Ca++

NO-

O2-

NOS

?PKCoxidation

ONOO-

O2-

*PKC

GAP43

↑release?

↑CaM

Retrograde Signaling in E-LTP

N M D AR ecep to r

m G lu R

P K C

E R K

R S K 2

m n k 1

G S K 3 B

eIF 4 E /eIF 2 B& o th er e IF 's

P o lyrib o so m eco m p lex

m R N ATarge tin g

F M R P(lo s t in F X M R )

C aM K II?

P K M z e ta

P S D -95as s o c ia ted p ro te in s

(S A P A P 4)M A P 1B

(1° ta rge t o f F M R P )A rc

C h an ge in S p in eS tru c tu re

M o rp h o lo gica l C h an ges

1° & 2° a lte ra tio n sin d en d ritic

p ro te in s y n th e s is

R ib o s o m a l S 6 P ro te inA K T m TO R

m R N A c a p b ind ing

4E B in d in gP ro te in

Tran s la tio nIn itia tio n

Figure 14

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

PerpetuatedStructural/Functional

Change

Altered Synthesis of

Specific Proteins=

The Trigger

Effector Protein Complex

=The Readout*

MEMORYSTORAGE

Constitutive Protein Synthesis Induced Protein Synthesis

*New Spine Structure,Potentiated Synapse,etc.

Memory-Causing Event

Dendritic Spine

“Housekeeping Proteins”

Constitutive EffectorProtein

Signal toSpecific Proteins

mRNA

NMDA Receptor

Altered Protein Synthesis as Trigger for Memory

Positive Feedback to

Synthesisor

Recruitment=

The MaintenanceMechanism

Blue Box 1

CAMKII as a Temporal Integrator

Blue Box 2

Presynaptic

Postsynaptic

NMDA Receptor

PKC

Presynaptic?

Release Process

Ca++

NOS

NO·

O2-

(Superoxide)

ONOO-

peroxynitrite?

Other Sources

cys{ }cys

Persistently Active PKC

Zn++ release

PKC

O2-

Ca++/CaM

Oxidative Activation of PKC in LTP

Blue Box 3

F A1 = Any o f a num be r o f 1 6 -2 0 c ar bo n fat ty ac i ds

F A2 = Typi c al l y Ar ac hi do ni c Ac i d i n p l as m a m e m br ane

C O O H

A ra ch ido n ic A cid

R =

O H O H

O H (PO 4)

O H (PO 4)O H

OI n o s ito l( I n o s ito l Ph o s ph a te s )

R = O C C

C O O H

NH 2

S e rin e

R = O C C NH 2 Eth a n o la m in e

R = O C C N(C H 3) 3+

C h o lin e

C C C

O O

C = O C = O

O P

O

=

O

O ¯

F A1 F A2

PL A 1 PL A 2

PL C

PL

D

R

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

Synaptictag

NMDAR

Synaptic Tagging and the E-LTP/ L-LTP Transition