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Alcohol-Induced Plasticity in Neuronal Circuits: NMDA Receptors and Homeostatic Plasticity

Explore the intricate relationship between chronic ethanol exposure and the brain's adaptive plasticity, focusing on NMDA receptors and the restoration of neuronal stability through homeostatic plasticity. The study delves into synaptic changes, dendritic spines, and structural plasticity in response to prolonged alcohol use. Understand how chronic ethanol exposure affects neuronal circuits and the underlying mechanisms involved in tolerance development and ethanol withdrawal.

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Alcohol-Induced Plasticity in Neuronal Circuits: NMDA Receptors and Homeostatic Plasticity

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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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