Combination of Haloperidol With UNC9994, β-arrestin-Biased Analog of Aripiprazole, Ameliorates Schizophrenia-Related Phenotypes Induced by NMDAR Deficit in Mice.

Background: Glutamatergic system dysfunction contributes to a full spectrum of schizophrenia-like symptoms, including the cognitive and negative symptoms that are resistant to treatment with antipsychotic drugs (APDs). Aripiprazole, an atypical APD, acts as a dopamine partial agonist, and its combination with haloperidol (a typical APD) has been suggested as a potential strategy to improve schizophrenia. Recently, an analog of aripiprazole, UNC9994, was developed.

Selective Enhancement of REM Sleep in Male Rats through Activation of Melatonin MT Receptors Located in the Locus Ceruleus Norepinephrine Neurons.

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS.

A miR-137-Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing.

Background: miR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-wide association studies have implicated miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing.

A complex relation between levels of adult hippocampal neurogenesis and expression of the immature neuron marker doublecortin.

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule β-arrestin-2 (β-Arr2) is required for the antidepressant-like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and survival of adult-born granule cells are absent in the β-Arr2 knockout (KO) mice. To our surprise, fluoxetine induced a dramatic upregulation of the number of doublecortin (DCX)-expressing cells in the β-Arr2 KO mice, indicating that this marker can be increased even though AHN is not.

Inhibition of glycogen synthase kinase 3 by lithium, a mechanism in search of specificity.

Inhibition of Glycogen synthase kinase 3 (GSK3) is a popular explanation for the effects of lithium ions on mood regulation in bipolar disorder and other mental illnesses, including major depression, cyclothymia, and schizophrenia. Contribution of GSK3 is supported by evidence obtained from animal and patient derived model systems. However, the two GSK3 enzymes, GSK3α and GSK3β, have more than 100 validated substrates.

Evidence of an interaction between and polymorphisms on levels of Negative Symptoms of Schizophrenia and their response to antipsychotics.

Background: Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, fragile X mental retardation syndrome-related 1 (FXR1) gene has been GWAS associated with SCZ.

Fxr1 regulates sleep and synaptic homeostasis.

The fragile X autosomal homolog 1 (Fxr1) is regulated by lithium and has been GWAS-associated with schizophrenia and insomnia. Homeostatic regulation of synaptic strength is essential for the maintenance of brain functions and involves both cell-autonomous and system-level processes such as sleep. We examined the contribution of Fxr1 to cell-autonomous homeostatic synaptic scaling and neuronal responses to sleep loss, using a combination of gene overexpression and Crispr/Cas9-mediated somatic knockouts to modulate gene expression.

D1 receptors in the anterior cingulate cortex modulate basal mechanical sensitivity threshold and glutamatergic synaptic transmission.

The release of dopamine (DA) into target brain areas is considered an essential event for the modulation of many physiological effects. While the anterior cingulate cortex (ACC) has been implicated in pain related behavioral processes, DA modulation of synaptic transmission within the ACC and pain related phenotypes remains unclear. Here we characterized a Crispr/Cas9 mediated somatic knockout of the D1 receptor (D1R) in all neuronal subtypes of the ACC and find reduced mechanical thresholds, without affecting locomotion and anxiety.

Region-specific effects of acute haloperidol in the human midbrain, striatum and cortex.

D2 autoreceptors provide an important regulatory mechanism of dopaminergic neurotransmission. However, D2 receptors are also expressed as heteroreceptors at postsynaptic membranes. The expression and the functional characteristics of both, D2 auto- and heteroreceptors, differ between brain regions.

Robust production of uniform human cerebral organoids from pluripotent stem cells.

Human cerebral organoid (hCO) models offer the opportunity to understand fundamental processes underlying human-specific cortical development and pathophysiology in an experimentally tractable system. Although diverse methods to generate brain organoids have been developed, a major challenge has been the production of organoids with reproducible cell type heterogeneity and macroscopic morphology. Here, we have directly addressed this problem by establishing a robust production pipeline to generate morphologically consistent hCOs and achieve a success rate of >80%.

Contribution of neuronal calcium sensor 1 (Ncs-1) to anxiolytic-like and social behavior mediated by valproate and Gsk3 inhibition.

Peripheral biomarker and post-mortem brains studies have shown alterations of neuronal calcium sensor 1 (Ncs-1) expression in people with bipolar disorder or schizophrenia. However, its engagement by psychiatric medications and potential contribution to behavioral regulation remains elusive. We investigated the effect on Ncs-1 expression of valproic acid (VPA), a mood stabilizer used for the management of bipolar disorder.

5-HT Receptor Antagonists in Neurologic and Neuropsychiatric Disorders: The Iceberg Still Lies beneath the Surface.

5-HT receptor antagonists, first introduced to the market in the mid-1980s, are proven efficient agents to counteract chemotherapy-induced emesis. Nonetheless, recent investigations have shed light on unappreciated dimensions of this class of compounds in conditions with an immunoinflammatory component as well as in neurologic and psychiatric disorders. The promising findings from multiple studies have unveiled several beneficial effects of these compounds in multiple sclerosis, stroke, Alzheimer disease, and Parkinson disease.

ACKR3 Regulation of Neuronal Migration Requires ACKR3 Phosphorylation, but Not β-Arrestin.

Phosphorylation of heptahelical receptors is thought to regulate G protein signaling, receptor endocytosis, and non-canonical signaling via recruitment of β-arrestins. We investigated chemokine receptor functionality under phosphorylation-deficient and β-arrestin-deficient conditions by studying interneuron migration in the embryonic cortex. This process depends on CXCL12, CXCR4, G protein signaling and on the atypical CXCL12 receptor ACKR3.

Motor learning deficits and striatal GSK-3 hyperactivity in Akt3 knockout mice.

Akt protein family (Akt1, Akt2 and Akt3) of serine/threonine kinases, also known as protein kinase B, are enzymes implicated in many physiological and pathological processes in the central nervous system. A striking feature of these enzymes is their ability to interact with several molecular targets such as the glycogen synthase kinase 3 (GSK-3). Among Akt isoforms, the Akt3 is significantly more expressed in the brain and the present investigation was designed to determine whether the Akt3/GSK-3 pathway plays a role in the learning of a complex motor skill.

Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects.

Antipsychotic drugs targeting dopamine neurotransmission are still the principal mean of therapeutic intervention for schizophrenia. However, about one third of people do not respond to dopaminergic antipsychotics. Genome wide association studies (GWAS), have shown that multiple genetic factors play a role in schizophrenia pathophysiology.

A fresh look at cortical dopamine D2 receptor expressing neurons.

The dopamine D2 receptor (DRD2) remains the principal target of antipsychotic drugs used for the management of schizophrenia and other psychotic disorders. This receptor is highly expressed within the basal ganglia, more specifically the striatal caudate nucleus and the nucleus accumbens. The general functions, signaling and behavioral contributions of striatal DRD2 are well understood.

Are FXR Family Proteins Integrators of Dopamine Signaling and Glutamatergic Neurotransmission in Mental Illnesses?

Dopamine receptors and related signaling pathways have long been implicated in pathophysiology and treatment of mental illnesses, including schizophrenia and bipolar disorder. Dopamine signaling may impact neuronal activity by modulation of glutamate neurotransmission. Recent evidence indicates a direct and/or indirect involvement of fragile X-related family proteins (FXR) in the regulation and mediation of dopamine receptor functions.

Mental Illnesses-Associated Fxr1 and Its Negative Regulator Gsk3β Are Modulators of Anxiety and Glutamatergic Neurotransmission.

Genetic variants of the fragile X mental retardation syndrome-related protein 1 ( have been associated to mood regulation, schizophrenia, and bipolar disorders. Nonetheless, genetic association does not indicate a functional link of a given gene to neuronal activity and associated behaviors. In addition, interaction between multiple genes is often needed to sculpt complex traits such as behavior.

Regulation of the Neuroligin-1 Gene by Clock Transcription Factors.

NEUROLIGIN-1 (NLGN1) is a postsynaptic adhesion molecule involved in the regulation of glutamatergic transmission. It has been associated with several features of sleep and psychiatric disorders. Our previous work suggested that transcription of the Nlgn1 gene could be regulated by the transcription factors CLOCK and BMAL1 because they bind to the Nlgn1 gene promoter in vivo.