TY - JOUR
T1 - A novel role of the WNT-dishevelled-GSK3β signaling cascade in the mouse nucleus accumbens in a social defeat model of depression
AU - Wilkinson, Matthew B.
AU - Dias, Caroline
AU - Magida, Jane
AU - Mazei-Robison, Michelle
AU - Lobo, Marykay
AU - Kennedy, Pamela
AU - Dietz, David
AU - Covington, Herbert
AU - Russo, Scott
AU - Neve, Rachael
AU - Ghose, Subroto
AU - Tamminga, Carol
AU - Nestler, Eric J.
PY - 2011/6/22
Y1 - 2011/6/22
N2 - Based on earlier gene expression and chromatin array data, we identified the protein, dishevelled (DVL)-2, as being regulated in the nucleus accumbens (NAc), a key brain reward region, in the mouse social defeat model of depression. Here, we validate these findings by showing that DVL2 mRNA and protein levels are downregulated in NAc of mice susceptible to social defeat stress, effects not seen in resilient mice. OtherDVLisoforms, DVL1 and DVL3, show similar patterns of regulation. Downregulation of DVL was also demonstrated in the NAc of depressed humans examined postmortem. Interestingly, several members of the WNT (Wingless)-DVL signaling cascade, including phospho-GSK3_ (glycogen synthase kinase-3_), also show significant downregulation in the NAc of susceptible, but not resilient, mice, demonstrating concerted regulation of this pathway in the NAc due to social defeat stress. By using viral-mediated gene transfer to overexpress a dominant-negative mutant of DVL in NAc, or by using a pharmacological inhibitor of DVL administered into this brain region, we show that blockade of DVL function renders mice more susceptible to social defeat stress and promotes depression like behavior in other assays. Similar prodepression-like effects were induced upon overexpressing GSK3_ in the NAc, while overexpressing a dominant-negative mutant of GSK3_ promoted resilience to social defeat stress. These findings are consistent with the knowledge that downregulation of DVL and phospho-GSK3_ reflects an increase in GSK3_ activity. These studies reveal a novel role for the DVL-GSK3β signaling pathway, acting within the brain's reward circuitry, in regulating susceptibility to chronic stress.
AB - Based on earlier gene expression and chromatin array data, we identified the protein, dishevelled (DVL)-2, as being regulated in the nucleus accumbens (NAc), a key brain reward region, in the mouse social defeat model of depression. Here, we validate these findings by showing that DVL2 mRNA and protein levels are downregulated in NAc of mice susceptible to social defeat stress, effects not seen in resilient mice. OtherDVLisoforms, DVL1 and DVL3, show similar patterns of regulation. Downregulation of DVL was also demonstrated in the NAc of depressed humans examined postmortem. Interestingly, several members of the WNT (Wingless)-DVL signaling cascade, including phospho-GSK3_ (glycogen synthase kinase-3_), also show significant downregulation in the NAc of susceptible, but not resilient, mice, demonstrating concerted regulation of this pathway in the NAc due to social defeat stress. By using viral-mediated gene transfer to overexpress a dominant-negative mutant of DVL in NAc, or by using a pharmacological inhibitor of DVL administered into this brain region, we show that blockade of DVL function renders mice more susceptible to social defeat stress and promotes depression like behavior in other assays. Similar prodepression-like effects were induced upon overexpressing GSK3_ in the NAc, while overexpressing a dominant-negative mutant of GSK3_ promoted resilience to social defeat stress. These findings are consistent with the knowledge that downregulation of DVL and phospho-GSK3_ reflects an increase in GSK3_ activity. These studies reveal a novel role for the DVL-GSK3β signaling pathway, acting within the brain's reward circuitry, in regulating susceptibility to chronic stress.
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U2 - 10.1523/JNEUROSCI.0039-11.2011
DO - 10.1523/JNEUROSCI.0039-11.2011
M3 - Article
C2 - 21697359
AN - SCOPUS:79959679248
SN - 0270-6474
VL - 31
SP - 9084
EP - 9092
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 25
ER -