Target For Antipsychotic Drugs Research Articles

New Therapeutic Targets and Drugs for Schizophrenia Beyond Dopamine D2 Receptor Antagonists.

Schizophrenia is a disease with a complex pathological mechanism that is influenced by multiple genes. The study of its pathogenesis is dominated by the dopamine hypothesis, as well as other hypotheses such as the 5-hydroxytryptamine hypothesis, glutamate hypothesis, immune-inflammatory hypothesis, gene expression abnormality hypothesis, and neurodevelopmental abnormality hypothesis. The first generation of antipsychotics was developed based on dopaminergic receptor antagonism, which blocks dopamine D2 receptors in the brain to exert antipsychotic effects. The second generation of antipsychotics acts by dual blockade of 5-hydroxytryptamine and dopamine receptors. From the third generation of antipsychotics onwards, the therapeutic targets for antipsychotic schizophrenia expanded beyond D2 receptor blockade to explore D2 receptor partial agonism and the antipsychotic effects of new targets such as D3, 5-HT1A, 5-HT7, and mGlu2/3 receptors. The main advantages of the second and third generation antipsychotics over first-generation antipsychotics are the reduction of side effects and the improvement of negative symptoms, and even though third-generation antipsychotics do not directly block D2 receptors, the modulation of the dopamine transmitter system is still an important part of their antipsychotic process. According to recent research, several receptors, including 5-hydroxytryptamine, glutamate, γ-aminobutyric acid, acetylcholine receptors and norepinephrine, play a role in the development of schizophrenia. Therefore, the focus of developing new antipsychotic drugs has shifted towards agonism or inhibition of these receptors. Specifically, the development of NMDARs stimulants, GABA receptor agonists, mGlu receptor modulators, cholinergic receptor modulators, 5-HT2C receptor agonists and alpha-2 receptor modulators has become the main direction. Animal experiments have confirmed the antipsychotic effects of these drugs, but their pharmacokinetics and clinical applicability still require further exploration. Research on alternative targets for antipsychotic drugs, beyond the dopamine D2 receptor, has expanded the potential treatment options for schizophrenia and gives an important way to address the challenge of refractory schizophrenia. This article aims to provide a comprehensive overview of the research on therapeutic targets and medications for schizophrenia, offering valuable insights for both treatment and further research in this field.

Histone deacetylase inhibitors mitigate antipsychotic risperidone-induced motor side effects in aged mice and in a mouse model of Alzheimer's disease.

Antipsychotic drugs are still widely prescribed to control various severe neuropsychiatric symptoms in the elderly and dementia patients although they are off-label use in the United States. However, clinical practice shows greater side effects and lower efficacy of antipsychotics for this vulnerable population and the mechanisms surrounding this aged-related sensitivity are not well understood. Our previous studies have shown that aging-induced epigenetic alterations may be involved in the increasing severity of typical antipsychotic haloperidol induced side effects in aged mice. Still, it is unknown if similar epigenetic mechanisms extend to atypical antipsychotics, which are most often prescribed to dementia patients combined with severe neuropsychiatric symptoms. In this study, we report that atypical antipsychotic risperidone also causes increased motor side effect behaviors in aged mice and 5xFAD mice. Histone deacetylase (HDAC) inhibitor Valproic Acid and Entinostat can mitigate the risperidone induced motor side effects. We further showed besides D2R, reduced expression of 5-HT2A, one of the primary atypical antipsychotic targets in the striatum of aged mice that are also mitigated by HDAC inhibitors. Finally, we demonstrate that specific histone acetylation mark H3K27 is hypoacetylated at the 5htr2a and Drd2 promoters in aged mice and can be reversed with HDAC inhibitors. Our work here establishes evidence for a mechanism where aging reduces expression of 5-HT2A and D2R, the key atypical antipsychotic drug targets through epigenetic alteration. HDAC inhibitors can restore 5-HT2A and D2R expression in aged mice and decrease the motor side effects in aged and 5xFAD mice.

The Role of G Protein-Coupled Receptors (GPCRs) and Calcium Signaling in Schizophrenia. Focus on GPCRs Activated by Neurotransmitters and Chemokines.

Schizophrenia is a common debilitating disease characterized by continuous or relapsing episodes of psychosis. Although the molecular mechanisms underlying this psychiatric illness remain incompletely understood, a growing body of clinical, pharmacological, and genetic evidence suggests that G protein-coupled receptors (GPCRs) play a critical role in disease development, progression, and treatment. This pivotal role is further highlighted by the fact that GPCRs are the most common targets for antipsychotic drugs. The GPCRs activation evokes slow synaptic transmission through several downstream pathways, many of them engaging intracellular Ca2+ mobilization. Dysfunctions of the neurotransmitter systems involving the action of GPCRs in the frontal and limbic-related regions are likely to underly the complex picture that includes the whole spectrum of positive and negative schizophrenia symptoms. Therefore, the progress in our understanding of GPCRs function in the control of brain cognitive functions is expected to open new avenues for selective drug development. In this paper, we review and synthesize the recent data regarding the contribution of neurotransmitter-GPCRs signaling to schizophrenia symptomology.

Functional Characterization of Prefrontal Cortical D2 Dopamine Receptor in Adult Mice

The dopamine D2 receptor (DRD2) remains the principal target of antipsychotic drugs used for the management of schizophrenia and other psychotic disorders. DRD2 in prefrontal cortex (PFC) has been at the centre of interest because of its involvement in regulation of cognitive and emotional processes and its regulation by antipsychotic drugs. However, further investigations of PFC DRD2 functions have been hindered by relatively low receptor expression, antibodies and ligand selectivity or limits of gene reporter systems.

Hyponatremia Following Antipsychotic Treatment: In Silico Pharmacodynamics Analysis of Spontaneous Reports From the US Food and Drug Administration Adverse Event Reporting System Database and an Updated Systematic Review.

BackgroundHyponatremia associated with antipsychotic drugs is a rare but potentially life-threatening adverse drug reaction; the underlying pharmacological mechanism has not yet been explained.MethodsWe investigated the relationship between pharmacological targets of antipsychotic drugs and the occurrence of hyponatremia by conducting a nested case-control study using the Food and Drug Administration Adverse Event Reporting System database. Multiple logistic regression was used to determine the associations between antipsychotics receptor occupancy and hyponatremia. We also performed a systematic review of clinical studies on this association.ResultsOf 139 816 reports involving at least 1 antipsychotic, 1.1% reported hyponatremia. Olanzapine was the most frequently suspected drug (27%). A significant positive association was found between dopamine D3, D4, and hyponatremia, while adrenergic α 1, serotonin 5-HT1A, and 5-HT2A receptor occupancies were negatively associated. A multivariable stepwise regression model showed that dopamine D3 (adj. odds ratio = 1.21; 95% CI = 1.09–1.34; P < .05) predicted the risk for hyponatremia (P < .05), while serotonin 5-HT2A occupancy (Adj. odds ratio = 0.78; 95% CI = 0.68–0.90; P < .01) exhibited a protective effect against hyponatremia. Among the 11 studies included in the systematic review, incidence rates of hyponatremia diverged between 0.003% and 86%, whereas the odds of developing hyponatremia from effect studies ranged between 0.83 and 3.47.ConclusionsAntipsychotic drugs having a combined modest occupancy for D3 and 5-HT2A receptors and higher levels of D3 receptor occupancy correspond to different degrees of risk for hyponatremia. Based on the few, relatively large-scale available studies, atypical antipsychotics have a more attenuated risk profile for hyponatremia.

Minds, Maps, Meanderings

In her book Mind Fixers: Psychiatry's Troubled Search for the Biology of Mental Illness, historian Anne Harrington challenges psychiatrists to embrace complexity. Her central message is that society has often projected a lot onto psychiatry, with our field far too eager to accept these and to fill an expertise void: at one point, with psychoanalytic grandiosity, later with overpromised, underperforming biological boasts and reified diagnostic labels. Echoing Foucault, Harrington invites us to avoid mistaking the name of the thing for the thing itself and to keep struggling for answers, embracing a slow science, marketing expertise humbly.2 Although some may feel defensive in their reading of Mind Fixers, I found it an invitation to recognize that the successes and failures of psychiatry's past are our inheritance. It is up to us to learn from this past, to be humbled and encouraged by it, and to examine how we are promoting our field in the present. We need to advertise that although many aspects of neural functioning elude us and although we rely on many of the same therapeutic practices from the past, we are not without direction for the future. For example, an elegant roadmap was laid out a year ago by Karolina Kauppi and colleagues wherein they combined a data set for schizophrenia risk genes and another set of genes associated with antipsychotic drug targets.3 Using this "network biology" approach, they identified four schizophrenia risk genes that were also antipsychotic drug targets (GRM3, DRD2, CHRM4, and CYP2D6); they also found several molecular targets that are not currently connected to antipsychotic drug treatment, providing researchers with some potential targets for novel therapeutics.4.

Isolation of Human Monoclonal scfv Antibody Specifically Recognizing the D2-5-Ht1a Heteromer.

Antibody phage display has become a useful technique for discovering and optimizing target-specific monoclonal antibodies suitable for many applications, including therapeutic ligands, which may act as direct pharmacological compounds or may be used as targeting ligands for controlled drug delivery. Recently, the D2-5-HT1A heteromer, which is formed by the dopamine D2 and serotonin 5-HT1A receptors has attracted attention as a potential target of antipsychotic drugs. Therefore, the aim of the study was to identify scFv monoclonal antibodies that are able to specifically recognize epitopes formed within the heteromer structure. Because both receptors are membrane proteins, it is important to conduct bio-panning experiments in the most natural conditions, in which the presented antigens (D2-5-HT1A heteromers) are in their native form and possibly in their best-preserved spatial structure. It has been shown here that phage display methodology can be successfully used in the preparation of monoclonal antibodies against dimers of membrane proteins. To separate phages specifically binding the D2-5-HT1A heteromer, the selection process using CHO+ cells with overexpression of both receptors was conducted. Phages that were bound to receptor monomers or other CHO-K1 cell surface proteins were eliminated as a result of negative selection by using CHO- cells expressing separate receptor monomers.

Mononuclear Cells of Peripheral Blood in vitro. A Model of Antipsychotic Therapy Personalization

The implementation of a unified strategy for prescribing antipsychotics has proved to be an ineffective approach to the treatment of mentally ill patients. The study of the efficiency of pharmacological drugs on models mimicking the individual pathophysiology of the patient is one means of personalized (predictive) therapy. We evaluated the mRNA level for the genes of the neurotransmitters’ receptors (ADR1B, HRH1, HTR2А, DRD1, DRD2, DRD4, and DRD5). These are targets of antipsychotic drugs; therefore, they can be used as the probable biomarkers of the success of the treatment of mental illnesses of schizophrenic spectrum. We used peripheral blood mononuclear cells (PBMC) in vitro as the therapeutic model. The study included 108 patients with a proved diagnosis of schizophrenia spectrum disorders, receiving a haloperidol or olanzapine as a monotherapy. The patients were divided into two groups based on their response to the pharmacotherapy (effective or ineffective). The response was estimated with psychometric analysis performed on 28 ± 2 days of the treatment. In the group with ineffective therapy, the level of expression of the studied genes in PBMC in vitro had increased with the presence of the antipsychotic drug, while, in the group of patients with positive dynamics of mental status normalization, the analyzed level of expression remained virtually unchanged. The highest significant differences for patients with different responses on the pharmacological treatment were observed for the ADR1B and HRH1 genes in the case of olanzapine therapy (Р = 0.004 and 0.038, respectively) and for the HTR2A gene in the case of haloperidol therapy (Р = 0.039). At the same time, basic levels of gene expression in non-cultivated PBMC were not associated with the patient’s response to therapy. Thus, the mRNA level for genes of neurotransmission in PBMC in vitro in the presence of antipsychotics can be proposed as a biomarker for predicting the pharmacotherapy outcome for mentally ill patients.

Molecular dynamics simulation of biased agonists at the dopamine D2 receptor suggests the mechanism of receptor functional selectivity

The dopamine D2 receptor (D2R) is the primary target for antipsychotic drugs. Besides schizophrenia, this receptor is linked to dementia, Parkinson’s disease, and depression. Recent studies have shown that β-arrestin biased agonists at this receptor treat schizophrenia with less side effects. Although the high resolution structure of this receptor exists, the mechanism of biased agonism at the receptor is unknown. In this study, dopamine, the endogenous unbiased G-protein agonist, MLS1547, a G-protein biased agonist, and UNC9975, a G-protein antagonist and a β-arrestin biased agonist, were docked to a homology model of the whole D2R including all flexible loops, and molecular dynamics simulations were conducted to study the potential mechanisms of biased agonism. Our thorough analysis on the protein–ligand interaction, secondary structure, tertiary structure, structure dynamics, and molecular switches of all three systems indicates that ligand binding to transmembrane 3 might be essential for G-protein recruitment, while ligand binding to transmembrane 6 might be essential for β-arrestin recruitment. Our analysis also suggests changes in both the secondary and the tertiary structures of TM5 and TM7, molecular switches and ICL3 flexibility are important in biased signaling.Communicated by Ramaswamy H. Sarma

Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs.

The data concerning antipsychotic-like activity of negative allosteric modulators (NAMs)/antagonists of mGlu7 receptors are limited. The only available ligands for this receptor are MMPIP and ADX71743. In the present studies, we used stable cell line expressing mGlu7 receptor and it was shown that both compounds dose-dependently potentiated forskolin elevated cAMP concentration in the T-REx 293 cells, showing their inverse agonist properties. Subsequently, pharmacokinetic studies were performed. Both compounds were given intraperitoneally (i.p.) at the dose of 10 mg/kg and reached Cmax 0.25–0.5 h after administration, and then they declined rapidly, ADX71743 being almost undetectable 2 h after administration, while the concentration of MMPIP was still observed, suggesting that the concentration of MMPIP was more stable. Finally, we investigated the role of both mGlu7 receptor NAMs in animal models of schizophrenia. Behavioral tests commonly used in antipsychotic drug discovery were conducted. Both tested compounds dose-dependently inhibited MK-801-induced hyperactivity (MMPIP at 15 mg/kg; ADX at 5 and 15 mg/kg) and DOI-induced head twitches (MMPIP at 5, 10, 15 mg/kg; ADX at 2.5, 5, 10 mg/kg). Moreover, the same effects were noticed in novel object recognition test, where MMPIP (5, 10, 15 mg/kg) and ADX71743 (1, 5, 15 mg/kg) reversed MK-801-induced disturbances. In the social interaction test, antipsychotic activity was observed only for ADX71743 (5, 15 mg/kg). ADX71743 at the dose 2.5 mg/kg reversed MK-801-induced disruption in prepulse inhibition while MMPIP at 10 mg/kg reversed MK-801-induced disruption in spatial delayed alternation. The present studies showed that mGlu7 receptor may be considered as a putative target for antipsychotic drugs, though more studies are needed due to limited number of available ligands.

Antipsychotic Drugs: From Receptor-binding Profiles to Metabolic Side Effects.

Background: Antipsychotic-induced metabolic side effects are major concerns in psychopharmacology and clinical psychiatry. Their pathogenetic mechanisms are still not elucidated.Methods: Herein, we review the impact of neurotransmitters on metabolic regulation, providing insights into antipsychotic-induced metabolic side effects.Results: Antipsychotic drugs seem to interfere with feeding behaviors and energy balance, processes that control metabolic regulation. Reward and energy balance centers in central nervous system constitute the cen-tral level of metabolic regulation. The peripheral level consists of skeletal muscles, the liver, the pancreas, the adipose tissue and neuroendocrine connections. Neurotransmitter receptors have crucial roles in metabolic regulation and they are also tar-gets of antipsychotic drugs. Interaction of antipsychotics with neurotransmitters could have both protective and harmful ef-fects on metabolism.Conclusion: Emerging evidence suggests that antipsychotics have different liabilities to induce obesity, diabetes and dyslipidemia. However this diversity cannot be explained merely by drugs’pharmacodynamic profiles, highlighting the need for further research

A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: the role of the dopamine transporter

Antipsychotic drugs are effective interventions in schizophrenia. However, the efficacy of these agents often decreases over time, which leads to treatment failure and symptom recurrence. We report that antipsychotic efficacy in rat models declines in concert with extracellular striatal dopamine levels rather than insufficient dopamine D2 receptor occupancy. Antipsychotic efficacy was associated with a suppression of dopamine transporter activity, which was reversed during failure. Antipsychotic failure coincided with reduced dopamine neuron firing, which was not observed during antipsychotic efficacy. Synaptic field responses in dopamine target areas declined during antipsychotic efficacy and showed potentiation during failure. Antipsychotics blocked synaptic vesicle release during efficacy but enhanced this release during failure. We found that the pharmacological inhibition of the dopamine transporter rescued antipsychotic drug treatment outcomes, supporting the hypothesis that the dopamine transporter is a main target of antipsychotic drugs and predicting that dopamine transporter blockers may be an adjunct treatment to reverse antipsychotic treatment failure.

Revisiting Antipsychotic Drug Actions Through Gene Networks Associated With Schizophrenia.

Antipsychotic drugs were incidentally discovered in the 1950s, but their mechanisms of action are still not understood. Better understanding of schizophrenia pathogenesis could shed light on actions of current drugs and reveal novel "druggable" pathways for unmet therapeutic needs. Recent genome-wide association studies offer unprecedented opportunities to characterize disease gene networks and uncover drug-disease relationships. Polygenic overlap between schizophrenia risk genes and antipsychotic drug targets has been demonstrated, but specific genes and pathways constituting this overlap are undetermined. Risk genes of polygenic disorders do not operate in isolation but in combination with other genes through protein-protein interactions among gene product. The protein interactome was used to map antipsychotic drug targets (N=88) to networks of schizophrenia risk genes (N=328). Schizophrenia risk genes were significantly localized in the interactome, forming a distinct disease module. Core genes of the module were enriched for genes involved in developmental biology and cognition, which may have a central role in schizophrenia etiology. Antipsychotic drug targets overlapped with the core disease module and comprised multiple pathways beyond dopamine. Some important risk genes like CHRN, PCDH, and HCN families were not connected to existing antipsychotics but may be suitable targets for novel drugs or drug repurposing opportunities to treat other aspects of schizophrenia, such as cognitive or negative symptoms. The network medicine approach provides a platform to collate information of disease genetics and drug-gene interactions to shift focus from development of antipsychotics to multitarget antischizophrenia drugs. This approach is transferable to other diseases.

FMRI correlates of jumping-to-conclusions in patients with delusions: Connectivity patterns and effects of metacognitive training.

BackgroundReasoning biases such as the jumping-to-conclusions bias (JTC) are thought to contribute to delusions. Interventions targeting these biases such as metacognitive training (MCT) may improve delusions. So far, it is not clear whether JTC depends on dopaminergic reward areas that constitute the main action locus of antipsychotic drugs, or on additional cortical areas. The present study aimed to investigate fMRI activation and functional connectivity patterns underlying JTC, and their changes following MCT, in patients with delusions.MethodsParticipants were 25 healthy individuals and 26 patients with current delusions who were either medication-free or on stable medication without sufficient response. We assessed (1) BOLD activity in the task-positive (TPN), task-negative (TNN), and subcortical reward network (RN); (2) Psychophysiological interactions (PPI) of peak activation areas.ResultsPresence of JTC (irrespective of group) was associated with lower RN activity during conclusion events, and with increased effective connectivity between TPN and TNN during draw events. Following MCT, changes were observed in TPN activity and in effective connectivity of inferior parietal cortex (part of the TPN) with all three target networks.ConclusionJTC is associated not only with reward system areas that constitute the main target of antipsychotic drugs, but also with cortical areas, particularly of the TPN.

The activity of the serotonin receptor 2C is regulated by alternative splicing.

The central nervous system-specific serotonin receptor 2C (5HT2C) controls key physiological functions, such as food intake, anxiety, and motoneuron activity. Its deregulation is involved in depression, suicidal behavior, and spasticity, making it the target for antipsychotic drugs, appetite controlling substances, and possibly anti-spasm agents. Through alternative pre-mRNA splicing and RNA editing, the 5HT2C gene generates at least 33 mRNA isoforms encoding 25 proteins. The 5HT2C is a G-protein coupled receptor that signals through phospholipase C, influencing the expression of immediate/early genes like c-fos. Most 5HT2C isoforms show constitutive activity, i.e., signal without ligand binding. The constitutive activity of 5HT2C is decreased by pre-mRNA editing as well as alternative pre-mRNA splicing, which generates a truncated isoform that switches off 5HT2C receptor activity through heterodimerization; showing that RNA processing regulates the constitutive activity of the 5HT2C system. RNA processing events influencing the constitutive activity target exon Vb that forms a stable double stranded RNA structure with its downstream intron. This structure can be targeted by small molecules and oligonucleotides that change exon Vb alternative splicing and influence 5HT2C signaling in mouse models, leading to a reduction in food intake. Thus, the 5HT2C system is a candidate for RNA therapy in multiple models of CNS disorders.

Investigation of chemical interactions of small peptides and vitamin substances at the developed dopamine D2 receptor models

IntroductionDopamine receptors perform various functions essential to vertebrate central nervous systems and they are the major targets of antipsychotic drugs. Our recent studies pioneered to perform molecular modeling studies of the dopamine D2 receptor (D2R), describing the mechanism and binding affinities of marketed antipsychotics into the active sites of the D2highR and D2LowR [1]. Another study provided significant information about changes of binding cavity properties of D2R [2].ObjectivesSince the marketed antipsychotics have serious side effects, we aim to explore ligands with better inhibition profiles on D2R with less unwanted outcomes. For this aim, we compare the effectiveness of the marketed drugs with small peptides and vitamin substances.AimsThe main goal of the research is to explore novel small molecules that inhibit D2R to be used in schizophrenia.MethodsIn this study, we used a large number of endogen vitamins and peptides with dopamine D2R active-inactive forms in monomeric-dimeric patterns to understand their interactions at the active sites of targets. Nineteen of antipsychotic drugs, which are widely used in schizophrenia treatment are selected as reference molecules. Molecular docking, molecular screening and molecular modeling approaches were used.ResultsSome of these endogen molecules showed similar or better inhibition profiles on D2R compared to the known standard inhibitors of the target.ConclusionsProposed molecules may be potent for D2 receptor inhibition with less side effects for the use for schizophrenia.Disclosure of interestThe authors have not supplied their declaration of competing interest.

GC-MS analysis and in-silico antipsychotic activity of Morinda citrifolia (Indian Noni)

GC-MS determination of bioactive components of Erythropalum scandens Bl., Bijdr.Sutha .S, Kalpana Devi .V, Mohan .V.R

M44 - Investigation of Genetic Variants Within Genes Targets of Antipsychotic Response And Their Signal Cascade In Schizophrenia And Antipsychotic Response

Background Schizophrenia (SCZ) is a devastating psychiatric disease that affects about 1% of the population and ranks among the top 10 causes of disability worldwide. Although environmental factors can play a relevant role in the development of SCZ, evidences from family, twin, and adoption studies suggest a strong genetic component in the etiology of the disease. Similarly, a genetic contribution for antipsychotic outcome has been suggested. In the present study we investigated the associations among two distinct groups of single nucleotide polymorphisms (SNPs) within 1) genes coding for molecular targets of antipsychotic drugs and 2) genes whose products were involved with the signal transduction of the primary molecular targets. Methods Two independent samples were investigated in this study. A Korean sample of 176 in-patients and 326 healthy controls and an Italian sample of 83 patients and 195 healthy controls. A total of 100 SNPs within 18 genes were analyzed in the two samples. We investigated 1) differences among genotypic and allelic frequencies in patients with SCZ compared with healthy control subjects and 2) possible influence of the SNPs under investigation on clinical improvement, as measured with the PANSS total scale in SCZ patients. Results In the Italian sample, rs12668837 within NCAPG2 and rs7439 within PKDCC showed a different allelic distribution between cases and controls. In the pharmacogenetic analysis, variants within CHRNA7, MAPK1 genes (which coding for antipsychotic targets) and variants within PLA2G4A, ESYT2 and HOMER1 genes (which are involved in the antipsychotic targets signal transduction) showed trends of association with antipsychotic response as measured by PANSS scale. Discussion Overall, our data suggest a possible role of these two groups of genes in both SCZ pathophysiology and antipsychotic response. A limited sample size and the consequent risk of false positive findings should be carefully taken into consideration when evaluating these results.

Endocytosis following dopamine D2 receptor activation is critical for neuronal activity and dendritic spine formation via Rabex-5/PDGFRβ signaling in striatopallidal medium spiny neurons.

Aberrant dopamine D2 receptor (D2R) activity is associated with neuropsychiatric disorders, making those receptors targets for antipsychotic drugs. Here, we report that novel signaling through the intracellularly localized D2R long isoform (D2LR) elicits extracellular signal-regulated kinase (ERK) activation and dendritic spine formation through Rabex-5/platelet-derived growth factor receptor-β (PDGFRβ)-mediated endocytosis in mouse striatum. We found that D2LR directly binds to and activates Rabex-5, promoting early-endosome formation. Endosomes containing D2LR and PDGFRβ are then transported to the Golgi apparatus, where those complexes trigger Gαi3-mediated ERK signaling. Loss of intracellular D2LR-mediated ERK activation decreased neuronal activity and dendritic spine density in striatopallidal medium spiny neurons (MSNs). In addition, dendritic spine density in striatopallidal MSNs significantly increased following treatment of striatal slices from wild-type mice with quinpirole, a D2R agonist, but those changes were lacking in D2LR knockout mice. Moreover, intracellular D2LR signaling mediated effects of a typical antipsychotic drug, haloperidol, in inducing catalepsy behavior. Taken together, intracellular D2LR signaling through Rabex-5/PDGFRβ is critical for ERK activation, dendritic spine formation and neuronal activity in striatopallidal MSNs of mice.

SZGR 2.0: a one-stop shop of schizophrenia candidate genes.

SZGR 2.0 is a comprehensive resource of candidate variants and genes for schizophrenia, covering genetic, epigenetic, transcriptomic, translational and many other types of evidence. By systematic review and curation of multiple lines of evidence, we included almost all variants and genes that have ever been reported to be associated with schizophrenia. In particular, we collected ∼4200 common variants reported in genome-wide association studies, ∼1000 de novo mutations discovered by large-scale sequencing of family samples, 215 genes spanning rare and replication copy number variations, 99 genes overlapping with linkage regions, 240 differentially expressed genes, 4651 differentially methylated genes and 49 genes as antipsychotic drug targets. To facilitate interpretation, we included various functional annotation data, especially brain eQTL, methylation QTL, brain expression featured in deep categorization of brain areas and developmental stages and brain-specific promoter and enhancer annotations. Furthermore, we conducted cross-study, cross-data type and integrative analyses of the multidimensional data deposited in SZGR 2.0, and made the data and results available through a user-friendly interface. In summary, SZGR 2.0 provides a one-stop shop of schizophrenia variants and genes and their function and regulation, providing an important resource in the schizophrenia and other mental disease community. SZGR 2.0 is available at https://bioinfo.uth.edu/SZGR/.