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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

The Thorny Side of Addiction:

Adaptive Plasticity and Dendritic Spines

Judson Chandler

Department of Neurosciences

Medical University of South Carolina


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

Peter W Kalivas and Charles O’Brien


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

NMDA Receptors: Subunits and membrane trafficking


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

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


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

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


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

*

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


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

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


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

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

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?


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

Phalloidin stained F-actin

Actin/NR1

Matus, Science 290:754, 2000

Dendritic Spines and Structural Plasticity


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

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


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

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


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

*

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


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

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


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

Control

EtOH

2Pal

EtOH + 2Pal

EtOH

+2Pal

Control

EtOH

2Pal

Density

*

##

Extrasynaptic

Synaptic

NR1/synapsin


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

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


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

*

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?


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

Chronic Ethanol-induced

Plasticity

versus

Toxicity

Novel object recognition


The thorny side of addiction adaptive plasticity and dendritic spines judson chandler

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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