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Abstract Making high‐quality dopamine (DA)‐producing cells for basic biological or small molecule screening studies is critical for the development of novel therapeutics for disorders of the ventral midbrain. Currently, many ventral midbrain assays have low signal‐to‐noise ratio due to low levels of cellular DA and the rate‐limiting enzyme of DA synthesis, tyrosine hydroxylase (TH), hampering discovery efforts. Using intensively characterized ventral midbrain cells derived from human skin, which demonstrate calcium pacemaking activity and classical electrophysiological properties, we show that an L‐type calcium agonist can significantly increase TH protein levels and DA content and release. Live calcium imaging suggests that it is the immediate influx of calcium occurring simultaneously in all cells that drives this effect. Genome‐wide expression profiling suggests that L‐type calcium channel stimulation has a significant effect on specific genes related to DA synthesis and affects expression of L‐type calcium receptor subunits from the CACNA1 and CACNA2D families. Together, our findings provide an advance in the ability to increase DA and TH levels to improve the accuracy of disease modeling and small molecule screening for disorders of the ventral midbrain, including Parkinson's disease.

Summary: Heterozygous loss-of-function mutations in GRIN2B, a subunit of the NMDA receptor, cause intellectual disability and language impairment. We developed clonal models of GRIN2B deletion and loss-of-function mutations in a region coding for the glutamate binding domain in human cells and generated neurons from a patient harboring a missense mutation in the same domain. Transcriptome analysis revealed extensive increases in genes associated with cell proliferation and decreases in genes associated with neuron differentiation, a result supported by extensive protein analyses. Using electrophysiology and calcium imaging, we demonstrate that NMDA receptors are present on neural progenitor cells and that human mutations in GRIN2B can impair calcium influx and membrane depolarization even in a presumed undifferentiated cell state, highlighting an important role for non-synaptic NMDA receptors. It may be this function, in part, which underlies the neurological disease observed in patients with GRIN2B mutations. : Mutations in GRIN2B cause intellectual disability and language impairments. In this study, Bell and colleagues engineer mutations in GRIN2B and repair a patient missense mutation to show an important role for GRIN2B and non-synaptic NMDA receptors in differentiating neural stem cells. Keywords: GRIN2B, NMDAR2B, NMDA, glutamate, iPSCs, CRISPR, CRISPR-Cas9, neurodevelopment, NPCs, neural stem cell

Early-life adversity is thought to increase the risk of psychopathology through epigenetic mechanisms. Here, the authors profile 6 histone marks, chromatin states and DNA methylation in the lateral amygdala in subjects with a history of early-life adversity.

It is not fully understood why some patients respond or do not respond to antidepressant treatment. Here the authors show that in the blood of individuals with depression, GPR56 expression increases in responders to antidepressant treatment, but not in non-responders.

Summary: Cocaine dependence is a chronic, relapsing disorder caused by lasting changes in the brain. Animal studies have identified cocaine-related alterations in striatal DNA methylation; however, it is unclear how methylation is related to cocaine dependence in humans. We generated methylomic profiles of the nucleus accumbens using human postmortem brains from a cohort of individuals with cocaine dependence and healthy controls (n = 25 per group). We found hypermethylation in a cluster of CpGs within the gene body of tyrosine hydroxylase (TH), containing a putative binding site for the early growth response 1 (EGR1) transcription factor, which is hypermethylated in the caudate nucleus of cocaine-dependent individuals. We replicated this finding and found it to be specific to striatal neuronal nuclei. Furthermore, this locus demonstrates enhancer activity which is attenuated by methylation and enhanced by EGR1 overexpression. These results suggest that cocaine dependence alters the epigenetic regulation of dopaminergic signaling genes.