Molecular Neuropsychiatry

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...

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...

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...

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.

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...

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...

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 CYP2D6 genetic variation. Here, we aimed to determine the potential benefit of pairing CYP2C19 and CYP2D6 testing with the five-step STAR*D algorithm...

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...

The Research Domain Criteria (RDoC) paradigm was launched 10 years ago as a superior approach for investigation of mental illness. RDoC conceptualizes normal human behavior, emotion, and cognition as dimensional, with mental illnesses as dimensional extremes. We suggest that RDoC may have value for understanding normal human psychology and some conditions plausibly construed as extremes of normal variation. By contrast, for the most serious of mental illnesses, including dementia, autism, schizophrenia, and bipolar disorder, we argue that RDoC is conceptually flawed...

A genome-wide significant association has been reported between non-coding variants at the dopamine D2 receptor ( DRD2 ) gene locus and schizophrenia. However, effects of identified schizophrenia risk alleles on DRD2 function are yet to be demonstrated. Using highly sensitive measures of allele-specific expression, we have assessed cis -regulatory effects associated with genotype at lead SNP rs2514218 on DRD2 expression in the adult human striatum. No significant differences were observed in the extent of allelic expression imbalance between samples that were genomic heterozygotes for rs2514218 (where cis -regulatory effects of the risk allele are compared with those of the non-risk allele within individual subjects) and samples that were homozygous for rs2514218 (where cis -regulatory effects of this SNP on each expressed DRD2 allele will be equal)...

Evidence from animal and human studies has linked myo -inositol (MI) with the pathophysiology and/or treatment of psychiatric disorders such as schizophrenia and bipolar disorder. However, there is still controversy surrounding the definitive role of MI in these disorders. Given that brain MI is differentially regulated by three transporters - SMIT1, SMIT2 and/or HMIT (encoded by the genes: SLC5A3, SLC5A11 , and SLC2A13 , respectively) - we used available datasets to describe the distribution in mouse and human brain of the different MI transporters and to examine changes in mRNA expression of these transporters in patients with schizophrenia and bipolar disorder...

The κ-opioid receptor (KOR) system has been implicated in the regulation of many behaviors including pain. While there are numerous studies suggesting KOR regulation of pain being mediated spinally, there have been reports of pain-like behaviors regulated by central KOR signaling. In particular, oxytocin-induced analgesia appears to be mediated by KOR receptors within the ventrolateral periaqueductal gray (vlPAG). We recently found that activation of dopamine (DA) neurons within the vlPAG is antinociceptive...

Around 300 million individuals are affected by major depressive disorder (MDD) in the world. Despite this high number of affected individuals, more than 50% of patients do not respond to antidepressants approved to treat MDD. Patients with MDD that do not respond to 2 or more first-line antidepressant treatments are considered to have treatment-resistant depression (TRD). Animal models of depression are important tools to better understand the pathophysiology of MDD as well as to help in the development of novel and fast antidepressants for TRD patients...

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Women are twice as likely as men to be diagnosed with major depressive disorder (MDD). Recent studies report distinct molecular changes in depressed men and women across mesocorticolimbic brain regions. However, it is unclear which sex-related factors drive distinct MDD-associated pathology. The goal of this study was to use mouse experimental systems to investigate sex-specific mechanisms underlying the distinct molecular profiles of MDD in men and women. We used unpredictable chronic mild stress to induce an elevated anxiety-/depressive-like state and "four core genotypes" (FCG) mice to probe for sex-specific mechanisms...

Alterations in synaptic signaling and plasticity occur during the refinement of neural circuits over the course of development and the adult processes of learning and memory. Synaptic plasticity requires the rearrangement of protein complexes in the postsynaptic density (PSD), trafficking of receptors and ion channels and the synthesis of new proteins. Activity-induced short Homer proteins, Homer1a and Ania-3, are recruited to active excitatory synapses, where they act as dominant negative regulators of constitutively expressed, longer Homer isoforms...

There is tremendous interest in the role of the neuroimmune system and inflammatory processes in substance use disorders (SUDs). Imaging biomarkers of the neuroimmune system in vivo provide a vital translational bridge between preclinical and clinical research. Herein, we examine two imaging techniques that measure putative indices of the neuroimmune system and review their application among SUDs. Positron emission tomography (PET) imaging of 18 kDa translocator protein availability is a marker associated with microglia...

Bipolar disorder (BD) is characterized by recurrent mood episodes, and circadian rhythm disturbances. Past studies have identified calcium channel genes as risk loci for BD. CACNA1C encodes an L-type calcium channel (LTCC) involved in the entrainment of circadian rhythms to light. Another calcium channel, i.e., the ryanodine receptor (RYR), is involved in -circadian phase delays. It is unknown whether variants in CACNA1C or other calcium channels contribute to the circadian phenotype in BD. We hypothesized that, by using temperature cycles, we could model circadian entrainment in fibroblasts from BD patients and controls to interrogate the circadian functions of LTCCs...

Loss of function mutations in SETD1A are the first experiment-wide significant findings to emerge from exome sequencing studies of schizophrenia. Although SETD1A is known to encode a histone methyltransferase, the consequences of reduced S ETD1A activity on gene expression in neural cells have, to date, been unknown. To explore transcriptional changes through which genetic perturbation of SETD1A could confer risk for schizophrenia, we have performed genome-wide gene expression profiling of a commonly used human neuroblastoma cell line in which SETD1A expression has been experimentally reduced using RNA interference (RNAi)...

Mutations in NHE6 (also termed SLC9A6 ) cause the X-linked neurological disorder Christianson syndrome (CS) in males. The purpose of this study was to examine the phenotypic spectrum of female carriers of NHE6 mutations. Twenty female carriers from 9 pedigrees were enrolled, ranging from approximately age 2 to 65. A subset of female carriers was assessed using standardized neuropsychological measures. Also, the association of NHE6 expression with markers of brain age was evaluated using 740 participants in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP)...