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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. 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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  1. The Thorny Side of Addiction: Adaptive Plasticity and Dendritic Spines Judson Chandler Department of Neurosciences Medical University of South Carolina

  2. Peter W Kalivas and Charles O’Brien

  3. NMDA Receptors: Subunits and membrane trafficking

  4. 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

  5. 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

  6. * 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

  7. 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

  8. 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

  9. 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?

  10. Phalloidin stained F-actin Actin/NR1 Matus, Science 290:754, 2000 Dendritic Spines and Structural Plasticity

  11. 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

  12. 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

  13. * 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

  14. 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

  15. Control EtOH 2Pal EtOH + 2Pal EtOH +2Pal Control EtOH 2Pal Density * ## Extrasynaptic Synaptic NR1/synapsin

  16. 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

  17. * 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?

  18. Chronic Ethanol-induced Plasticity versus Toxicity Novel object recognition

  19. 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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