The Thorny Side of Addiction: Adaptive Plasticity and Dendritic Spines

Judson Chandler

Department of NeurosciencesMedical University of South Carolina

Peter W Kalivas and Charles O’Brien

NMDA Receptors: Subunits and membrane trafficking

EtOH

EtOH

Prolonged ethanol(Homeostatic plasticity restores

stability to neuronal circuits; underlies tolerance development)

EtOH

EtOH

Acute ethanol(Instability of neuronal circuits)

Normal balance

Ethanol withdrawal(Hyper-excitability;

promotes aberrant plasticity)

Inhibitory ExcitatoryGABAergic Glutamatergic

Alcohol Tolerance and Homeostatic Plasticity

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

In Vitro Model of Chronic Alcohol Exposure

EtOH NR1 syn overlay

NR1 syn overlayControl

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GluR1

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Percent Colocalization

GluR1 Cluster Size

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SizeColocalization

Amplitude Frequency

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02468101214161820

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Amplitude, pA Frequency, Hz

AMPA mEPSC

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Control EtOH Withdrawn0.00.10.20.30.40.50.60.70.80.91.0

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Current, pA/pF

Extrasynaptic NMDA Currents

•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.

Summary of findings

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

Con EtOH NMDAEtOH+NMDA

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NR2A NR2B

PSD-95

Molecular model of ethanol-induce plasticity

Chronic activity blockade

PSD Signaling Complex PSD

Signaling Complex

NR2BPSD-95

Spine enlargement

Actincycling

PSD Signaling Complex

recruitment

“learning spines” “memory spines”(more plastic, but less stable) (more stable, but less plastic)

Repeated EtOH exposure and

withdrawalexperiences

PSD Signaling Complex

recruitment

•Does this model have in vivo validity?

Control Ethanol0.00.10.20.30.40.50.6 *

NM

DA

/AM

PA ra

tio

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

Everitt and Robbins, 2005

Novel object recognition

Chronic Ethanol-induced Plasticity

versusToxicity

Ezekiel Carpenter-HylandNick Luong

Patrick Mulholland John Woodward

Sven KroenerHoward Becker

Kenneth AbernathyLuca Pellicoro

Jeremy Seamans Chris Lapish

NIAAANIHABMRF

Acknowledgements