Aripiprazole and haloperidol protect neurite lesions via reducing excessive D2R-DISC1 complex formation

Peng Zheng, Minmin Hu, Yuanyi Xie, Yinghua Yu, Hanna Jaaro-Peled, Xu Feng Huang

Research output: Contribution to journalArticle

Abstract

Dopamine D2 receptor (D2R) hyperactivity causes altered brain development and later produces onset of symptoms mimicking schizophrenia. It is known that D2R interacts with disrupted in schizophrenia 1 (DISC1); however, the effect of D2R-DISC1 interaction in intracellular signalling and neurite growth has not been studied. This study investigated the effect of D2R over-activation on Akt-GSK3β signalling and neurite morphology in cortical neurons. Over-activation of D2Rs caused neurite lesions, which were associated with decreased protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) phosphorylation in cortical neurons. The antipsychotic drug aripiprazole was more effective in the prevention of neurite lesions than haloperidol. Unlike haloperidol, aripiprazole prevented downregulation of phospho (p) Akt-pGSK3β induced by D2R hyperactivity, indicating involvement of different pathways. D2Rs were hyperactive in cortical neurons of mice with DISC1 mutation, which caused more severe neurite lesions in cortical neurons treated with quinpirole. Immunofluorescent staining for Ca2+/calmodulin-dependent protein kinase II (CaMKII) confirmed that cortical pyramidal neurons were involved in the D2R hyperactivity-induced neurite lesions. Using the fluorescence resonance energy transfer (FRET) technique, we provide direct evidence that D2R hyperactivity led to D2R-DISC1 complex formation, which altered pGSK3β signalling. This study showed that D2R hyperactivity-induced D2R-DISC1 complex formation is associated with decreased pAkt-pGSK3β signalling and in turn, caused neurite impairment. Aripiprazole and haloperidol prevented the impairment of neurite growth but appeared to do so via different intracellular signalling pathways.

Original languageEnglish (US)
Pages (from-to)59-69
Number of pages11
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume92
DOIs
StatePublished - Jun 8 2019

Fingerprint

Neurites
Haloperidol
Schizophrenia
Neurons
Quinpirole
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Proto-Oncogene Proteins c-akt
Fluorescence Resonance Energy Transfer
Dopamine D2 Receptors
Aripiprazole
Pyramidal Cells
Growth
Antipsychotic Agents
Down-Regulation
Phosphorylation
Staining and Labeling
Mutation
Brain

Keywords

  • Antipsychotic drug
  • D2 receptor
  • D2R-DISC1 complex
  • GSK3β
  • Neurite growth

ASJC Scopus subject areas

  • Pharmacology
  • Biological Psychiatry

Cite this

Aripiprazole and haloperidol protect neurite lesions via reducing excessive D2R-DISC1 complex formation. / Zheng, Peng; Hu, Minmin; Xie, Yuanyi; Yu, Yinghua; Jaaro-Peled, Hanna; Huang, Xu Feng.

In: Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 92, 08.06.2019, p. 59-69.

Research output: Contribution to journalArticle

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