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Ethanol exposure induces neonatal neurodegeneration by enhancing CB1R Exon1 histone H4K8 acetylation and up-regulating CB1R function causing neurobehavioral abnormalities in adult mice.

Subbanna S, Nagre NN, Umapathy NS, Pace BS, Basavarajappa BS - Int. J. Neuropsychopharmacol. (2014)

Bottom Line: We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively.We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice.The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression.

View Article: PubMed Central - PubMed

Affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY (Drs Subbanna, Nagre, and Basavarajappa); Vascular Biology Center, Georgia Regents University, Augusta, GA (Dr Umapathy); Department of Pediatrics, Georgia Regents University, Augusta, GA (Dr Pace); New York State Psychiatric Institute, New York, NY (Dr Basavarajappa); Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY (Dr Basavarajappa).

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P7 ethanol treatment impairs and SR pretreatment rescues impaired spatial memory performance as measured by the Y maze. Discrimination ratio (preference for the novel arm over the familiar or other arm: Novel/Novel + Other) for arm entries (a and c) and dwell time (b and d) of S+V- and E+V-treated mice with or without SR in the Y maze at 1h and 24h after the first encounter with the partially-opened maze. The dashed line indicates chance performance (0.5). (e) The percentage of animals selecting the novel arm as the first choice is shown for S+V- and E+V-treated mice with or without SR at 1h and 24h after the first encounter with the partially-opened maze. Each point is the mean ± SEM (n = 8 mice/group). Two-way ANOVA with Bonferroni’s post hoc test: ***p < 0.001 vs. S + V; #p < 0.05 vs. E + V. Discrimination ratio (preference for the novel arm over the familiar or other arm: Novel/Novel + Other) for arm entries (f and h) and dwell time (g and i) of S+CB1RWT, E+CB1RWT, S+CB1RKO, and E+CB1RKO mice in the Y maze at 1h and 24h after the first encounter with the partially-opened maze. The dashed line indicates chance performance (0.5). (j) The percentage of animals selecting the novel arm as the first choice is shown for S+CB1RWT, E+CB1RWT, S+CB1RKO, and E+CB1RKO mice at 1h and 24h after the first encounter with the partially-opened maze. Each point is the mean ± SEM (n = 8 mice/group). Two-way ANOVA with Bonferroni’s post hoc test: ***p < 0.001 vs. S + V; #p≤ 0.01 vs. E ± V; $ p ≤ 0.01 vs. S ± CB1RWT; @ p ≤ 0.01 vs. S ± CB1RWT.
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Figure 8: P7 ethanol treatment impairs and SR pretreatment rescues impaired spatial memory performance as measured by the Y maze. Discrimination ratio (preference for the novel arm over the familiar or other arm: Novel/Novel + Other) for arm entries (a and c) and dwell time (b and d) of S+V- and E+V-treated mice with or without SR in the Y maze at 1h and 24h after the first encounter with the partially-opened maze. The dashed line indicates chance performance (0.5). (e) The percentage of animals selecting the novel arm as the first choice is shown for S+V- and E+V-treated mice with or without SR at 1h and 24h after the first encounter with the partially-opened maze. Each point is the mean ± SEM (n = 8 mice/group). Two-way ANOVA with Bonferroni’s post hoc test: ***p < 0.001 vs. S + V; #p < 0.05 vs. E + V. Discrimination ratio (preference for the novel arm over the familiar or other arm: Novel/Novel + Other) for arm entries (f and h) and dwell time (g and i) of S+CB1RWT, E+CB1RWT, S+CB1RKO, and E+CB1RKO mice in the Y maze at 1h and 24h after the first encounter with the partially-opened maze. The dashed line indicates chance performance (0.5). (j) The percentage of animals selecting the novel arm as the first choice is shown for S+CB1RWT, E+CB1RWT, S+CB1RKO, and E+CB1RKO mice at 1h and 24h after the first encounter with the partially-opened maze. Each point is the mean ± SEM (n = 8 mice/group). Two-way ANOVA with Bonferroni’s post hoc test: ***p < 0.001 vs. S + V; #p≤ 0.01 vs. E ± V; $ p ≤ 0.01 vs. S ± CB1RWT; @ p ≤ 0.01 vs. S ± CB1RWT.

Mentions: In our second behavioral test, we examined spatial recognition memory using the Y-maze. Two-way ANOVA revealed that saline- and SR-treated mice entered more frequently into (Arm Entry: 1h, F3,21 = 21, p < 0.01; 24h, F3,21 = 26, p < 0.01) and spent more time in (Dwell Time: 1h, F3,21 = 61, p < 0.01; 24h, F3,21 = 22, p < 0.01) the novel, previously unvisited arm of the maze. In contrast, P7 ethanol-treated mice showed a reduced preference toward the novel arm (p < 0.01) and spent less time (Dwell Time: p < 0.01) in the novel arm compared to P7 saline-treated mice in both the 1h (Figure 8a and b) and 24h (Figure 8c and d) retention trials. SR pre-treatment rescued ethanol-induced impairments in the preference for the novel arm (p < 0.01) and time spent (p < 0.01) in the novel arm in both the 1 and 24h retention trials. Although all saline- and SR-treated mice (combined 1 and 24h) selected the novel arm as the first choice, ethanol-treated animals showed a reduced preference for the novel arm (Figure 8e), which this was prevented by SR pretreatment (F3,45 = 50, p < 0.01). while CB1RKO mice showed an enhanced preference for the novel arm (Arm Entry, p < 0.001) and spent more time in the novel arm (Dwell Time, p < 0.001) compared to WT mice in both the 1h (Figure 8f and g) and 24h retention trials (Figure 8h and i). In addition, all saline- and ethanol-treated CB1RKO mice (combined 1 and 24h) selected the novel arm as the first choice (Figure 8j).


Ethanol exposure induces neonatal neurodegeneration by enhancing CB1R Exon1 histone H4K8 acetylation and up-regulating CB1R function causing neurobehavioral abnormalities in adult mice.

Subbanna S, Nagre NN, Umapathy NS, Pace BS, Basavarajappa BS - Int. J. Neuropsychopharmacol. (2014)

P7 ethanol treatment impairs and SR pretreatment rescues impaired spatial memory performance as measured by the Y maze. Discrimination ratio (preference for the novel arm over the familiar or other arm: Novel/Novel + Other) for arm entries (a and c) and dwell time (b and d) of S+V- and E+V-treated mice with or without SR in the Y maze at 1h and 24h after the first encounter with the partially-opened maze. The dashed line indicates chance performance (0.5). (e) The percentage of animals selecting the novel arm as the first choice is shown for S+V- and E+V-treated mice with or without SR at 1h and 24h after the first encounter with the partially-opened maze. Each point is the mean ± SEM (n = 8 mice/group). Two-way ANOVA with Bonferroni’s post hoc test: ***p < 0.001 vs. S + V; #p < 0.05 vs. E + V. Discrimination ratio (preference for the novel arm over the familiar or other arm: Novel/Novel + Other) for arm entries (f and h) and dwell time (g and i) of S+CB1RWT, E+CB1RWT, S+CB1RKO, and E+CB1RKO mice in the Y maze at 1h and 24h after the first encounter with the partially-opened maze. The dashed line indicates chance performance (0.5). (j) The percentage of animals selecting the novel arm as the first choice is shown for S+CB1RWT, E+CB1RWT, S+CB1RKO, and E+CB1RKO mice at 1h and 24h after the first encounter with the partially-opened maze. Each point is the mean ± SEM (n = 8 mice/group). Two-way ANOVA with Bonferroni’s post hoc test: ***p < 0.001 vs. S + V; #p≤ 0.01 vs. E ± V; $ p ≤ 0.01 vs. S ± CB1RWT; @ p ≤ 0.01 vs. S ± CB1RWT.
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Figure 8: P7 ethanol treatment impairs and SR pretreatment rescues impaired spatial memory performance as measured by the Y maze. Discrimination ratio (preference for the novel arm over the familiar or other arm: Novel/Novel + Other) for arm entries (a and c) and dwell time (b and d) of S+V- and E+V-treated mice with or without SR in the Y maze at 1h and 24h after the first encounter with the partially-opened maze. The dashed line indicates chance performance (0.5). (e) The percentage of animals selecting the novel arm as the first choice is shown for S+V- and E+V-treated mice with or without SR at 1h and 24h after the first encounter with the partially-opened maze. Each point is the mean ± SEM (n = 8 mice/group). Two-way ANOVA with Bonferroni’s post hoc test: ***p < 0.001 vs. S + V; #p < 0.05 vs. E + V. Discrimination ratio (preference for the novel arm over the familiar or other arm: Novel/Novel + Other) for arm entries (f and h) and dwell time (g and i) of S+CB1RWT, E+CB1RWT, S+CB1RKO, and E+CB1RKO mice in the Y maze at 1h and 24h after the first encounter with the partially-opened maze. The dashed line indicates chance performance (0.5). (j) The percentage of animals selecting the novel arm as the first choice is shown for S+CB1RWT, E+CB1RWT, S+CB1RKO, and E+CB1RKO mice at 1h and 24h after the first encounter with the partially-opened maze. Each point is the mean ± SEM (n = 8 mice/group). Two-way ANOVA with Bonferroni’s post hoc test: ***p < 0.001 vs. S + V; #p≤ 0.01 vs. E ± V; $ p ≤ 0.01 vs. S ± CB1RWT; @ p ≤ 0.01 vs. S ± CB1RWT.
Mentions: In our second behavioral test, we examined spatial recognition memory using the Y-maze. Two-way ANOVA revealed that saline- and SR-treated mice entered more frequently into (Arm Entry: 1h, F3,21 = 21, p < 0.01; 24h, F3,21 = 26, p < 0.01) and spent more time in (Dwell Time: 1h, F3,21 = 61, p < 0.01; 24h, F3,21 = 22, p < 0.01) the novel, previously unvisited arm of the maze. In contrast, P7 ethanol-treated mice showed a reduced preference toward the novel arm (p < 0.01) and spent less time (Dwell Time: p < 0.01) in the novel arm compared to P7 saline-treated mice in both the 1h (Figure 8a and b) and 24h (Figure 8c and d) retention trials. SR pre-treatment rescued ethanol-induced impairments in the preference for the novel arm (p < 0.01) and time spent (p < 0.01) in the novel arm in both the 1 and 24h retention trials. Although all saline- and SR-treated mice (combined 1 and 24h) selected the novel arm as the first choice, ethanol-treated animals showed a reduced preference for the novel arm (Figure 8e), which this was prevented by SR pretreatment (F3,45 = 50, p < 0.01). while CB1RKO mice showed an enhanced preference for the novel arm (Arm Entry, p < 0.001) and spent more time in the novel arm (Dwell Time, p < 0.001) compared to WT mice in both the 1h (Figure 8f and g) and 24h retention trials (Figure 8h and i). In addition, all saline- and ethanol-treated CB1RKO mice (combined 1 and 24h) selected the novel arm as the first choice (Figure 8j).

Bottom Line: We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively.We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice.The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression.

View Article: PubMed Central - PubMed

Affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY (Drs Subbanna, Nagre, and Basavarajappa); Vascular Biology Center, Georgia Regents University, Augusta, GA (Dr Umapathy); Department of Pediatrics, Georgia Regents University, Augusta, GA (Dr Pace); New York State Psychiatric Institute, New York, NY (Dr Basavarajappa); Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY (Dr Basavarajappa).

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Related in: MedlinePlus