dopaminergic neurons schizophrenia iPSCs

Trace amine-associated receptors (TAARs), which were discovered only in 2001, are known to be involved in the regulation of a spectrum of neuronal processes and may play a role in the pathogenesis of a number of neuropsychiatric diseases, such as schizophrenia and others. We have previously shown that TAARs also have interconnections with the regulation of neurogenesis and, in particular, with the neurogenesis of dopamine neurons, but the exact mechanisms of this are still unknown. In our work we analyzed the expression of TAARs (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8 and TAAR9) in cells from the human substantia nigra and ventral tegmental areas and in human pluripotent stem cells at consecutive stages of their differentiation to dopaminergic neurons, using RNA sequencing data from open databases, and TaqMan PCR data from the differentiation of human induced pluripotent stem cells in vitro...

Multiple integrative studies have been performed to identify the potential target genes of the non-coding schizophrenia (SCZ) risk variants. However, all the integrative studies used expression quantitative trait loci (eQTL) data from bulk tissues. Considering the cell type-specific regulatory effect of many genetic variants, it is important to conduct integrative studies using cell type-specific eQTL data. Here, we conduct a Mendelian randomization (MR) study by integrating genome-wide associations of SCZ (74,776 cases and 101,023 controls) and eQTL data (N = 215) from dopaminergic neurons, which were differentiated from human-induced pluripotent stem cell (iPSC) lines...

The use of patient-derived induced pluripotent stem cells (iPSCs) and their neural derivatives is becoming increasingly important in the study of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, peripheral neuropathy, and so on. Increasingly, iPSC-derived neurons also reveal key pathways and signaling defects in psychiatric disorders such as autism spectrum disorders, schizophrenia, and bipolar disorder. With recent advances in CRISPR/Cas9-mediated genome editing technology, patient-derived iPSCs with disease-causing mutations can be corrected into "isogenic control lines," and these can be differentiated into neural derivatives with identical genetic background...

Negative symptoms (NS) represent a heterogeneous dimension of schizophrenia (SCZ), associated with a poor functional outcome. A dysregulated dopamine (DA) system, including a reduced D1 receptor activation in the prefrontal cortex, DA hypoactivity in the caudate and alterations in D3 receptor activity, seems to contribute to the pathogenesis of NS. However, failure to take into account the NS heterogeneity has slowed down progress in research on their neurobiological correlates and discoveries of new effective treatments...

Dopaminergic (DA) neurons are involved in many critical functions within the central nervous system (CNS), and dopamine neurotransmission impairment underlies a wide range of disorders from motor control deficiencies, such as Parkinson's disease (PD), to psychiatric disorders, such as alcoholism, drug addictions, bipolar disorders, schizophrenia and depression. Neural stem cell-based technology has potential to play an important role in developing efficacious biological and small molecule therapeutic products for disorders with dopamine dysregulation...

The nucleus accumbens (NAc) shell is closely associated with reward, psychiatric disorders (depression or schizophrenia), and drug abuse. Dopamine, released from the ventral tegmental area, is involved in these physiological functions and pathophysiological changes of NAc shell. Medium spiny neurons (MSNs), which are only GABAergic projection neurons in NAc, also innervate adjacent MSNs, forming the lateral inhibition network. Previous studies demonstrate that dopamine suppresses the lateral inhibition via D2 -like (D2 and D3 ) receptors...

Schizophrenia (SZ) is a devastating mental disorder afflicting 1% of the population. Recent genome-wide association studies (GWASs) of SZ have identified >100 risk loci. However, the causal variants/genes and the causal mechanisms remain largely unknown, which hinders the translation of GWAS findings into disease biology and drug targets. Most risk variants are noncoding, thus likely regulate gene expression. A major mechanism of transcriptional regulation is chromatin remodeling, and open chromatin is a versatile predictor of regulatory sequences...

The human dopamine receptor D2 (DRD2) has been implicated in the pathophysiology of schizophrenia and other neuropsychiatric disorders. Most antipsychotic drugs influence dopaminergic transmission through blocking dopamine receptors, primarily DRD2. We report here the post-transcriptional regulation of DRD2 expression by two brain-expressed microRNAs (miRs), miR-326 and miR-9, in an ex vivo mode, and show the relevance of miR-mediated DRD2 expression regulation in human dopaminergic neurons and in developing human brains...

One of the prevailing hypotheses suggests schizophrenia as a neurodevelopmental disorder, involving dysfunction of dopaminergic and glutamatergic systems. Accumulating evidence suggests mitochondria as an additional pathological factor in schizophrenia. An attractive model to study processes related to neurodevelopment in schizophrenia is reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) and differentiating them into different neuronal lineages. iPSCs from three schizophrenia patients and from two controls were reprogrammed from hair follicle keratinocytes, because of their accessibility and common ectodermal origin with neurons...

Two distinct defects are thought to be important for the pathophysiology of schizophrenia. One is an increase of D2 receptors (D2Rs) in the striatum and another is a decrease in the GABAergic function in the prefrontal cortex (PFC). Whether these two defects are functionally linked is not known. We previously reported that selective overexpression of D2Rs in the striatum of the mouse causes behavioral abnormality associated with PFC functions. Using patch-clamp recording, we find that overexpression of D2Rs in the striatum affects inhibitory transmission in the PFC and dopamine (DA) sensitivity...

Dopamine (DA) receptors are the principal targets of drugs used in the treatment of schizophrenia. Among the five DA receptor subtypes, the D(4) subtype is of particular interest because of the relatively high affinity of the atypical neuropleptic clozapine for D(4) compared with D(2) receptors. GABA-containing neurons in the thalamic reticular nucleus (TRN) and globus pallidus (GP) express D(4) receptors. TRN neurons receive GABAergic afferents from globus pallidus (GP), substantia nigra pars reticulata (SNr), and basal forebrain as well as neighboring TRN neuron collaterals...