Prevention of Neurite Spine Loss Induced by Dopamine D2 Receptor Overactivation in Striatal Neurons

Peng Zheng; Qian Peter Su; Dayong Jin; Yinghua Yu; Xu-Feng Huang

doi:10.3389/fnins.2020.00642

Prevention of Neurite Spine Loss Induced by Dopamine D2 Receptor Overactivation in Striatal Neurons

Front Neurosci. 2020 Jun 23:14:642. doi: 10.3389/fnins.2020.00642. eCollection 2020.

Authors

Peng Zheng¹, Qian Peter Su², Dayong Jin², Yinghua Yu³, Xu-Feng Huang¹

Affiliations

¹ Illawarra Health and Medical Research Institute (IHMRI) and School of Medicine, University of Wollongong, Wollongong, NSW, Australia.
² Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.
³ Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, China.

Abstract

Psychosis has been considered a disorder of impaired neuronal connectivity. Evidence for excessive formation of dopamine D2 receptor (D2R) - disrupted in schizophrenia 1 (DISC1) complexes has led to a new perspective on molecular mechanisms involved in psychotic symptoms. Here, we investigated how excessive D2R-DISC1 complex formation induced by D2R agonist quinpirole affects neurite growth and dendritic spines in striatal neurons. Fluorescence resonance energy transfer (FRET), stochastic optical reconstruction microscopy (STORM), and cell penetrating-peptide delivery were used to study the cultured striatal neurons from mouse pups. Using these striatal neurons, our study showed that: (1) D2R interacted with DISC1 in dendritic spines, neurites and soma of cultured striatal neurons; (2) D2R and DISC1 complex accumulated in clusters in dendritic spines of striatal neurons and the number of the complex were reduced after application of TAT-D2pep; (3) uncoupling D2R-DISC1 complexes by TAT-D2pep protected neuronal morphology and dendritic spines; and (4) TAT-D2pep prevented neurite and dendritic spine loss, which was associated with restoration of expression levels of synaptophysin and PSD-95. In addition, we found that Neuropeptide Y (NPY) and GSK3β were involved in the protective effects of TAT-D2pep on the neurite spines of striatal spiny projection neurons. Thus, our results may offer a new strategy for precisely treating neurite spine deficits associated with schizophrenia.

Keywords: D2R–DISC1 complex; GABA; Neuropeptide Y; cell penetrating-peptide; schizophrenia; synaptic spine.