CRMP2 mediates GSK3β actions in the striatum on regulating neuronal structure and mania-like behavior

Wonju Kim, Seong Yeon Won, Bong June Yoon

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


Background: Genetic and physiological studies have implicated the striatum in bipolar disorder (BD). Although Glycogen synthase kinase 3 beta (GSK3β) has been suggested to play a role in the pathophysiology of BD since it is inhibited by lithium, it remains unknown how GSK3β activity might be involved. Therefore we examined the functional roles of GSK3β and one of its substrates, CRMP2, within the striatum. Methods: Using CRISPR-Cas9 system, we specifically ablated GSK3β in the striatal neurons in vivo and in vitro. Sholl analysis was performed for the structural studies of medium spiny neurons (MSNs) and amphetamine-induced hyperlocomotion was measured to investigate the effects of gene ablations on the mania-like symptom of BD. Results: GSK3β deficiency in cultured neurons and in neurons of adult mouse brain caused opposite patterns of neurite changes. Furthermore, specific knockout of GSK3β in the MSNs of the indirect pathway significantly suppressed amphetamine-induced hyperlocomotion. We demonstrated that these phenotypes of GSK3β ablation were mediated by CRMP2, a major substrate of GSK3β. Limitations: Amphetamine-induced hyperlocomotion only partially recapitulate the symptoms of BD. It requires further study to examine whether abnormality in GSK3β or CRMP2 is also involved in depression phase of BD. Additionally, we could not confirm whether the behavioral changes observed in GSK3β-ablated mice were indeed caused by the cellular structural changes observed in the striatal neurons. Conclusion: Our results demonstrate that GSK3β and its substrate CRMP2 critically regulate the neurite structure of MSNs and their functions specifically within the indirect pathway of the basal ganglia network play a critical role in manifesting mania-like behavior of BD. Moreover, our data also suggest lithium may exert its effect on BD through a GSK3β-independent mechanism, in addition to the GSK3β inhibition-mediated mechanism.

Original languageEnglish
Pages (from-to)1079-1088
Number of pages10
JournalJournal of Affective Disorders
Publication statusPublished - 2019 Feb 15

Bibliographical note

Funding Information:
This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, & Future Planning of the Republic of Korea ( NRF-2012R1A1A2009456 , NRF-2014R1A2A1A11053247 ) and a Korea University ( K1608411 ) research grant to BJY.

Publisher Copyright:
© 2018 Elsevier B.V.


  • Bipolar disorder
  • CRMP2
  • Dendritic spine
  • GSK3β
  • Medium spiny neuron
  • Striatum

ASJC Scopus subject areas

  • Clinical Psychology
  • Psychiatry and Mental health


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