Molecular Neuropsychiatry最新文献

Microglia are the primary innate immune cell type in the brain that have been implicated in the pathogenesis of several neurodegenerative and neuropsychiatric disorders, most notably Alzheimer's disease (AD) and schizophrenia. Microglia generated from human induced pluripotent stem cells (hiPSCs) represent a promising in vitro cellular model for studying the neuroimmune interactions involved in these disorders. Among several methods of generating -hiPSC-derived microglia (iMG) - varying in duration and resultant purity - a recent protocol by Brownjohn et al. [Stem Cell Reports. 2018 Apr;10(4):1294-307] is particularly simple and efficient. However, the replicability of this method, transcriptomic similarity of these iMG to primary adult microglia, and their genetic relevance to disease (i.e., enrichment of disease risk loci in genes preferentially expressed in these cells) remains unclear. Using two hiPSC lines, we demonstrated that Brownjohn's protocol can rapidly generate iMG that morphologically and functionally resembled microglia. The iMG cells we generated were found to be transcriptionally similar to previously reported iMG, as well as fetal and adult microglia. Furthermore, by using cell type-specific gene expression to partition disease heritability, we showed that iMG cells are genetically relevant to AD but found no significant enrichments of risk loci of Parkinson's disease, schizophrenia, major depressive disorder, bipolar disorder, autism spectrum disorder, or body mass index. Across a range of neuronal and immune cell types, we found only iMG, primary microglia, and microglia-like cell types exhibited a significant enrichment for AD heritability. Our results thus support the use of iMG as a human cellular model for understanding AD biology and underlying genetic factors, as well as for developing and efficiently screening new therapeutics.

PTEN is a lipid and protein phosphatase that regulates cell growth and survival. Mutations to PTEN are highly penetrant for autism spectrum disorder (ASD). Here, we briefly review the evidence linking PTEN mutations to ASD and the mouse models that have been used to study the role of PTEN in neurodevelopment. We then focus on the cellular phenotypes associated with PTEN loss in neurons, highlighting the role PTEN plays in neuronal proliferation, migration, survival, morphology, and plasticity.

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) algorithm is the most recognized protocol-based care approach for moderate to severe depression. However, its implementation results in one-third of individuals receiving modest to no symptom remission. One possible explanation is the inter-individual differences in antidepressant metabolism due to CYP2C19 and CYP2D6genetic variation. Here, we aimed to determine the potential benefit of pairing CYP2C19 and CYP2D6testing with the five-step STAR*D algorithm. To estimate the proportion of individuals that could benefit from CYP2C19 and CYP2D6 testing, we simulated the STAR*D algorithm using ethnicity-specific phenotype (e.g., metabolizer status) frequencies published by the Clinical Pharmacogenetics Implementation Consortium and census data from the Canada and the US. We found that up to one-third of the US and Canadian populations being treated for depression could benefit from the addition of CYP2C19and CYP2D6 genetic testing. The potential benefit varied for each step of the algorithm and for each province, territory, and state. CYP2C19 genotyping had the greatest potential impact within the first two steps of the algorithm, while CYP2D6 genotyping had the most notable impact in Steps 3, 4, and 5. Our findings suggest the implementation of CYP2C19and CYP2D6 genetic testing alongside the STAR*D treatment algorithm may improve depression treatment outcomes in Canada and the US.

Sleep disturbance affects about 75% of depressed individuals and is associated with poorer patient outcomes. The genetics in this field is an emerging area of research. Thus far, only core circadian genes have been examined in this context. We expanded on this by performing a genome-wide association study (GWAS) followed by a preplanned hypothesis-driven analysis with 27 genes associated with the biology of sleep. All participants were diagnosed by their referring physician, completed the Beck Depression Inventory (BDI), and the Udvalg for Kliniske Undersogelser Side Effect Rating Scale at baseline. Our phenotype consisted of replies to 3 questions from these questionnaires. From standard GWAS chip data, imputations were performed. Baseline total BDI scores (n = 364) differed significantly between those with and those without sleep problems. We were unable to find any significant GWAS hits although our top hit was for changes in sleep and an intergenic marker near SNX18 (p = 1.06 × 10^-6). None of the markers in our hypothesis-driven analysis remained significant after applying Bonferroni corrections. Our top finding among these genes was for rs13019460 of Neuronal PAS Domain Protein 2 with changes in sleep (p = 0.0009). Overall, both analyses were unable to detect any significant associations in our modest sample though we did find some interesting preliminary associations worth further exploration.

Bipolar disorder (BD) is a neuropsychiatric mood disorder characterized by recurrent episodes of mania and depression in addition to disruptions in sleep, energy, appetite, and cognitive functions-rhythmic behaviors that typically change on daily cycles. BD symptoms can also be provoked by seasonal changes, sleep, and/or circadian disruption, indicating that chronobiological factors linked to the circadian clock may be a common feature in the disorder. Research indicates that BD exists on a clinical spectrum, with distinct subtypes often intersecting with other psychiatric disorders. This heterogeneity has been a major challenge to BD research and contributes to problems in diagnostic stability and treatment outcomes. To address this heterogeneity, we propose that chronobiologically related biomarkers could be useful in classifying BD into objectively measurable phenotypes to establish better diagnoses, inform treatments, and perhaps lead to better clinical outcomes. Presently, we review the biological basis of circadian time keeping in humans, discuss the links of BD to the circadian clock, and pre-sent recent studies that evaluated chronobiological measures as a basis for establishing BD phenotypes. We conclude that chronobiology may inform future research using other novel techniques such as genomics, cell biology, and advanced behavioral analyses to establish new and more biologically based BD phenotypes.

Glutamate is implicated in the neuropathology of both major depressive disorder and bipolar disorder. Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the mammalian brain, removing glutamate from the synaptic cleft and transporting it into glia for recycling. It is thereby the principal regulator of extracellular glutamate levels and prevents neuronal excitotoxicity. EAAT2 is a promising target for elucidating the mechanisms by which the glutamate-glutamine cycle interacts with neuronal systems in mood disorders. Forty EAAT2 studies (published January 1992-January 2018) were identified via a systematic literature search. The studies demonstrated that chronic stress/steroids were most commonly associated with decreased EAAT2. In rodents, EAAT2 inhibition worsened depressive behaviors. Human EAAT2 expression usually decreased in depression, with some regional brain differences. Fewer data have been collected regarding the roles and regulation of EAAT2 in bipolar disorder. Future directions for research include correlating EAAT2 and glutamate levels in vivo, elucidating genetic variability and epigenetic regulation, clarifying intracellular protein and pharmacologic interactions, and examining EAAT2 in different bipolar mood states. As part of a macromolecular complex within glia, EAAT2 may contribute significantly to intracellular signaling, energy regulation, and cellular homeostasis. An enhanced understanding of this system is needed.

The retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) gene encodes a ciliary protein that is critical for processes related to brain development, including development of left-right asymmetry, sonic hedgehog signaling, and neural tube formation. RPGRIP1L is a risk factor for retinal degeneration, and rare, deleterious variants in the RPGRIP1L gene cause Joubert syndrome and Meckel syndrome, both autosomal recessive disorders. These syndromes are characterized by dysfunctional primary cilia that result in abnormal development - and even lethality in the case of Meckel syndrome. Genetic studies have also implicated RPGRIP1L in psychiatric disorders by suggestive findings from genome-wide association studies and findings from rare-variant exome analyses for bipolar disorder and de novo mutations in autism. In this study we identify a common variant in RPGRIP1L, rs7203525, that influences alternative splicing, increasing the inclusion of exon 20 of RPGRIP1L. We detected this alternative splicing association in human postmortem brain tissue samples and, using a minigene assay combined with in vitro mutagenesis, confirmed that the alternative splicing is attributable to the alleles of this variant. The predominate RPGRIP1L isoform expressed in adult brains does not contain exon 20; thus, a shift to include this exon may impact brain function.

Numerous genetic variants have been shown to be associated with antipsychotic response and adverse effects of schizophrenia treatment. However, the clinical application of these findings is limited. The aim of this narrative review is to summarize the most recent publications and recommendations related to the genetics of antipsychotic treatment and shed light on the clinical utility of pharmacogenetics/pharmacogenomics (PGx). We reviewed the literature on PGx studies with antipsychotic drugs (i.e., antipsychotic response and adverse effects) and commonly used commercial PGx tools for clinical practice. Publications and reviews were included with emphasis on articles published between January 2015 and April 2018. We found 44 studies focusing on antipsychotic response and 45 studies on adverse effects (e.g., antipsychotic-induced weight gain, movement disorders, hormonal abnormality, and clozapine-induced agranulocytosis/granulocytopenia), albeit with mixed results. Overall, several gene variants related to antipsychotic response and adverse effects in the treatment of patients with schizophrenia have been reported, and several commercial pharmacogenomic tests have become available. However, further well-designed investigations and replication studies in large and well-characterized samples are needed to facilitate the application of PGx findings to clinical practice.