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

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

doi:10.3389/fnins.2020.00642

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.

Highlights

Schizophrenia is a severe mental disorder that affects thinking and behavior
Our study showed that: (1) D2 receptor (D2R) interacted with disrupted in schizophrenia 1 (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 transcriptional activator (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
These nanoscale findings demonstrated that TAT-D2pep inhibits excessive D2R–DISC1 complex formation caused by D2R overactivation in dendritic spines

Summary

Introduction

Schizophrenia is a severe mental disorder that affects thinking and behavior. Neuroimaging studies have revealed neurobiological deficits in schizophrenia patients and psychosis has been considered as a disorder of impaired neuronal connections (Rae et al, 2017). Striatal dopamine D2 receptor (D2R) hyperactivity is predominantly responsible for psychosis in schizophrenia (Howes and Kapur, 2009). Administration of the D2R-specific agonist quinpirole can induce “hallucinatory-like” behaviors and cognitive decline in monkeys (Arnsten et al, 1995) and dramatically inhibit neurodevelopment of cortical and hippocampal neurons (Reinoso et al, 1996; Jia et al, 2013). These studies suggest that striatal D2R hyperactivity accounts for the neuro-pathogenesis of psychosis, the mechanism that underlies increased D2R activity remains to be elucidated. D2R is highly expressed in the striatum and striatal D2 receptor

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