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

Fig

ure

1

Release

Process

*PKC

AMPAR

NMDAR

Phosphorylation

& Insertion

Ca++

Retrograde

Messenger?

*CaMKII

*PKMzeta

*PKC

Synaptic Tag

K+ Channels

Protein Synthesis

?

?

* = Persistently Activated

Cytoskeleton

Changes

?

?

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

Calmodulin

Binding

286

Autonomous

Activity

305/306

Inhibitory

A

B C

Structure of CAMKII

Figure 4

NMDA

Receptor

CaMKII

Transient CaMKII

Activation

Thr 286

Autophosphorylation

(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

d Delta

e Epsilon

h Eta

q Theta

m Mu

Novel

l/i Lambda/Iota

z Zeta

Atypical

a alpha

bI/bII Beta

g Gamma

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

PKMz mRNA Formation from Internal Promoter

within PKCz Gene

Figure 10

PKMz 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 PKCs

Direct, irreversible covalent modification by reactive

oxygen species Effector phosphorylation

PKMz 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

actinin

CaMKII*

CaMKII

Ca++ trigger

for E-LTP

NM

DA

R

AM

PA

R

src

CaMKII*PKC*

PSD-95

* = Autophosphorylated CaMKII, Autonomous PKC

Stabilization Stabilization

?Membrane

insertion

Membrane

insertion

Glutamate Receptor Insertion and

Stabilization in E-LTP

Figure 13

NMDA

Receptor

Ca++

NO-

O2-

NOS

?PKC

oxidation

ONOO-

O2-

*PKC

↑release

?

↑CaM

Retrograde Signaling in E-LTP

NMDA

Receptor

mGluR

PKC

ERK

RSK2

mnk1

GSK3B

eIF4E/eIF2B

& other eIF's

Polyribosome

complex

mRNA

Targeting

FMRP(lost in FXMR)

CaMKII?

PKMzeta

PSD-95

associated proteins

(SAPAP4)

MAP1B

(1° target of FMRP)Arc

Change in Spine

Structure

Morphological Changes

1° & 2° alterations

in dendritic

protein synthesis

Ribosomal S6 ProteinAKT mTOR

mRNA cap binding

4E Binding

Protein

Translation

Initiation

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

SynthesisInduced 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·

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

FA1= Any of a number of 16-20

carbon fatty acids

FA2= Typically Arachidonic Acid

in plasma membraneCOOH

Arachidonic Acid

R =

OH OH

OH (PO4)

OH (PO4)OH

OInositol

(Inositol Phosphates)

R = O C C

COOH

NH2

Serine

R = O C C NH2Ethanolamine

R = O C C N(CH3)3

+Choline

C C C

O O

C = O C = O

O P

O

=

O

O¯

FA1 FA2

PLA1 PLA2

PLC

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

Synaptic

tag

NMDAR

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