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The Thorny Side of Addiction: Adaptive Plasticity and Dendritic Spines Judson Chandler Department of Neurosciences Medical University of South Carolina. Peter W Kalivas and Charles O’Brien. NMDA Receptors: Subunits and membrane trafficking. Inhibitory. Excitatory. Glutamatergic.

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The Thorny Side of Addiction: Adaptive Plasticity and Dendritic Spines Judson Chandler

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The Thorny Side of Addiction:

Adaptive Plasticity and Dendritic Spines

Judson Chandler

Department of Neurosciences

Medical University of South Carolina


Peter W Kalivas and Charles O’Brien


NMDA Receptors: Subunits and membrane trafficking


Inhibitory

Excitatory

Glutamatergic

GABAergic

EtOH

Acute ethanol

(Instability of neuronal circuits)

EtOH

EtOH

Prolonged ethanol

(Homeostatic plasticity restores

stability to neuronal circuits; underlies

tolerance development)

EtOH

Ethanol withdrawal

(Hyper-excitability;

promotes aberrant plasticity)

Alcohol Tolerance and Homeostatic Plasticity

Normal balance


In Vitro Model of Chronic Alcohol Exposure

Primary rat hippocampal neurons

Used for experimentation when fully mature (2-3 weeks in vitro)

Chronic ethanol exposure in sealed vapor chambers

Evaluated by IHC/confocal imaging & electrophysiology


*

16

14

Control

#

EtOH

12

EtOH+NMDA

10

NR1 Cluster Size

(# Pixels/Cluster)

8

6

4

2

0

Synaptic

Extrasynaptic

Size

Control

overlay

NR1

syn

NR1

NR1

syn

overlay

EtOH

Density

*

12

Control

10

EtOH

8

EtOH+NMDA

# NR1 Cluster/10 µM

6

*#

4

2

0

Synaptic

Extrasynaptic


Control

EtOH

Size

Density

*

20

*

12

18

Control

16

Control

10

14

EtOH

NR2B

EtOH

8

12

NR2B Cluster Size

(# Pixels/Cluster)

# NR2B

Clusters/10 µm

*

10

6

8

*

6

4

4

2

2

0

0

Extrasynaptic

Synaptic

Extrasynaptic

Synaptic

Control

EtOH

Colocalization

Size

100

90

14

80

12

70

GluR1

10

60

Percent Colocalization

GluR1 Cluster Size

(# pixels/cluster

50

8

40

6

30

4

20

2

10

0

0

Control

Control

Ethanol

Ethanol


Spontaneous NMDA EPSC

AMPA mEPSC

1.0

0.9

Control

20

20

0.8

Control

0.7

0.4

1000

*

18

0.6

18

EtOH

0.5

EtOH

0.4

*

16

16

0.3

0.2

750

0.3

14

14

0.1

0.0

Frequency, Hz

12

12

Frequency, Hz

Amplitude, pA

10

500

10

0.2

Amplitude, pA

8

8

6

6

250

0.1

4

4

2

2

0

0.0

0

0

Amplitude

Frequency

Amplitude

Frequency

60

40

Current, pA/pF

20

Control

EtOH

0

10

-6

10

-5

10

-4

10

-3

[NMDA], M

NMDA mEPSC

Extrasynaptic NMDA Currents

*

NMDA/AMPA

Current Ratio

Control

EtOH

Withdrawn


Summary of findings

  • Prolonged ethanol exposure results in the enhancement of NR2B-containing NMDA receptors selectively at the synapse.

  • No changes in AMPA receptors.

  • Activity and PKA-dependent.

  • Slowly reverses upon ethanol removal.

  • Electrophysiological observations correlated with confocal image analysis confirming functional plasticity.

Is there a corresponding structural component of this homeostatic response to chronic alcohol exposure?


Phalloidin stained F-actin

Actin/NR1

Matus, Science 290:754, 2000

Dendritic Spines and Structural Plasticity


Control

EtOH

actin

**

##

*

EtOH+

NMDA

*

#

*

EtOH+

NMDA

**

**

% Neurons with large spines

@

*

EtOH (mM)

EtOH+

NMDA

Con

EtOH

NMDA

Density

Size

F-Actin Clusters

(# pixels.cluster)

# F-actin Clusters/10 uM

Actin


EtOH+

NMDA

Cont

NMDA

EtOH

Control

PSD-95

PSD-95/synapsin

EtOH

Density

Size

*

*

#

*

PSD-95 Cluster Size

(# pixels/cluster)

#

#PSD-95 Clusters/10 uM

#

Synaptic

Extrasynaptic

Synaptic

Extrasynaptic

Extrasynaptic

Synaptic

Extrasynaptic

Synaptic


*

F-Actin/PSD-95

% colocalization

EtOH

Control

Control

EtOH

Actin

PSD-95

2um

Density

**

Size

**

F-Actin Cluster Size

(# pixels/cluster)

# F-Actin Clusters/10 uM

With PSD-95

With PSD-95

Without PSD-95

Without PSD-95


50

45

40

#

35

30

25

20

15

10

5

0

EtOH+

2Pal

2Pal

Cont

EtOH

*

9

#

8

**

7

6

5

4

3

2

1

0

EtOH+

2Pal

2Pal

Cont

EtOH

**

Actin

PSD-95

Size

Control

Control

# pixels/cluster

EtOH

2Pal

Density

2Pal

EtOH+2Pal

# clusters/10um

2um


Control

EtOH

2Pal

EtOH + 2Pal

EtOH

+2Pal

Control

EtOH

2Pal

Density

*

##

Extrasynaptic

Synaptic

NR1/synapsin


Actin

cycling

NR2B

PSD-95

recruitment

PSD Signaling Complex

Repeated EtOH exposure and

withdrawal

experiences

“memory spines”

“learning spines”

(more stable, but less plastic)

(more plastic, but less stable)

Molecular model of ethanol-induce plasticity

Chronic activity blockade

Spine enlargement

NR2B

NR2A

PSD-95

PSD Signaling Complex

PSD Signaling Complex


*

0.6

0.5

0.4

NMDA/AMPA ratio

0.3

0.2

recruitment

0.1

PSD Signaling Complex

0.0

Control

Ethanol

  • How do these homeostatic changes impact synaptic plasticity in the context of the addiction neurocircuitry?

Everitt and Robbins, 2005

  • Does this model have in vivo validity?


Chronic Ethanol-induced

Plasticity

versus

Toxicity

Novel object recognition


Acknowledgements

Ezekiel Carpenter-Hyland

Nick Luong

Patrick Mulholland

John Woodward

Sven Kroener

Howard Becker

Kenneth Abernathy

Luca Pellicoro

Jeremy Seamans

Chris Lapish

NIAAA

NIH

ABMRF


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