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

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.

Dopamine receptor D2 regulates GLUA1-containing AMPA receptor trafficking and central sensitization through the PI3K signaling pathway in a male rat model of chronic migraine

“…However, the effects of DRD2 and the PI3K pathway on electrophysiological activity in the TNC in CM rats have not been explored, which is a limitation of this study and will be our focus in future studies. In addition, we used NMDA instead of AMPA to establish the model of neuronal excitation [ 32 ] taking into account the neurotoxicity mediated by AMPA [ 61 ] and the observation that NMDA can also induce the increased expression of GLUA1-containing AMPARs on the membrane surface of neurons, which is pertinent to the purpose of this study [ 18 , 62 ].…”

“…Previous research has proven that DRD2 can modulate the firing of spinal neurons and thus alleviate pain behavior in neuropathic pain models [ 15 – 17 ]. An in-vitro study proved that DRD2 can regulate the dendritic density and dendritic spine morphology in striatal and hippocampal neurons [ 18 , 19 ]. In addition, several studies have reported that DRD2 can regulate the phosphorylation of the AMPA receptor [ 20 ] and alleviate AMPA receptor-mediated neurotoxicity [ 21 ].…”

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

“…This peculiar interaction could represent a potential D2R-mediated unconventional MOA at the dopamine receptor. In contrast, uncoupling D2R-DISC1 interaction, through the trans-activator of transcription (TAT)-D2pep (TAT-D2pep), reduced the previously discussed effect, resulting in a neuroprotective and preventive effect for neurite outgrowth and dendritic spines by associating with the downregulation of synaptophysin and PSD-95 expression [ 369 ].…”