Identification and characterization of human KALRN mRNA and Kalirin protein isoforms.

Kalirin is a multidomain protein with important roles in neurite outgrowth, and synaptic spine formation and remodeling. Genetic and pathophysiological links with various neuropsychiatric disorders associated with synaptic dysfunction and cognitive impairment have sparked interest in its potential as a pharmacological target. Multiple Kalirin proteoforms are detected in the adult human brain, yet we know little about the diversity of the transcripts that encode them or their tissue profiles.

CACNA1C (Ca1.2) and other L-type calcium channels in the pathophysiology and treatment of psychiatric disorders: Advances from functional genomics and pharmacoepidemiology.

A role for voltage-gated calcium channels (VGCCs) in psychiatric disorders has long been postulated as part of a broader involvement of intracellular calcium signalling. However, the data were inconclusive and hard to interpret. We review three areas of research that have markedly advanced the field.

New drug targets in psychiatry: Neurobiological considerations in the genomics era.

After a period of withdrawal, pharmaceutical companies have begun to reinvest in neuropsychiatric disorders, due to improvements in our understanding of these disorders, stimulated in part by genomic studies. However, translating this information into disease insights and ultimately into tractable therapeutic targets is a major challenge. Here we consider how different sources of information might be integrated to guide this process.

Catechol-O-methyltransferase activity does not influence emotional processing in men.

Background: Catechol-O-methyltransferase (COMT) regulates cortical dopaminergic transmission and prefrontal-dependent cognitive function. However, its role in other cognitive processes, including emotional processing, is relatively unexplored. We therefore investigated the separate and interactive influences of COMT inhibition and ValMet (rs4680) genotype on performance on an emotional test battery.

Long read sequencing reveals novel isoforms and insights into splicing regulation during cell state changes.

Background: Alternative splicing is a key mechanism underlying cellular differentiation and a driver of complexity in mammalian neuronal tissues. However, understanding of which isoforms are differentially used or expressed and how this affects cellular differentiation remains unclear. Long read sequencing allows full-length transcript recovery and quantification, enabling transcript-level analysis of alternative splicing processes and how these change with cell state.

Kalirin as a Novel Treatment Target for Cognitive Dysfunction in Schizophrenia.

The cognitive dysfunction experienced by patients with schizophrenia represents a major unmet clinical need. We believe that enhancing synaptic function and plasticity by targeting kalirin may provide a novel means to remediate these symptoms. Karilin (a protein encoded by the KALRN gene) has multiple functional domains, including two Dbl homology (DH) guanine exchange factor (GEF) domains, which act to enhance the activity of the Rho family guanosine triphosphate (GTP)-ases.

Gabapentin and pregabalin in bipolar disorder, anxiety states, and insomnia: Systematic review, meta-analysis, and rationale.

The gabapentinoids, gabapentin, and pregabalin, target the αδ subunits of voltage-gated calcium channels. Initially licensed for pain and seizures, they have become widely prescribed drugs. Many of these uses are off-label for psychiatric indications, and there is increasing concern about their safety, so it is particularly important to have good evidence to justify this usage.

Targeting synaptic plasticity in schizophrenia: insights from genomic studies.

Patients with schizophrenia experience cognitive dysfunction and negative symptoms that do not respond to current drug treatments. Historical evidence is consistent with the hypothesis that these deficits are due, at least in part, to altered cortical synaptic plasticity (the ability of synapses to strengthen or weaken their activity), making this an attractive pathway for therapeutic intervention. However, while synaptic transmission and plasticity is well understood in model systems, it has been challenging to identify specific therapeutic targets for schizophrenia.

Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility.

Dopamine plays a crucial role in adaptive behavior, and dysfunctional dopamine is implicated in multiple psychiatric conditions characterized by inflexible or inconsistent choices. However, the precise relationship between dopamine and flexible decision making remains unclear. One reason is that, while many studies have focused on the activity of dopamine neurons, efficient dopamine signaling also relies on clearance mechanisms, notably the dopamine transporter (DAT), which predominates in striatum, and catechol-O-methyltransferase (COMT), which predominates in cortex.

Induced Pluripotent Stem Cells in Psychiatry: An Overview and Critical Perspective.

A key challenge in psychiatry research is the development of high-fidelity model systems that can be experimentally manipulated to explore and test pathophysiological mechanisms of illness. In this respect, the emerging capacity to derive neural cells and circuits from human induced pluripotent stem cells (iPSCs) has generated significant excitement. This review aims to provide a critical appraisal of the potential for iPSCs in illuminating pathophysiological mechanisms in the context of other available technical approaches.

Long read transcript profiling of ion channel splice isoforms.

Alternative splicing of RNA transcripts allows a single gene to generate multiple products and is a key means of generating functionally diverse voltage-gated ion channels. Splicing can be regulated according to cell type, cell state, and stage of development to produce a bespoke complement of protein isoforms. Characterizing the identities of full-length transcript isoforms is essential in order to fully understand a gene's expression and function.

Benchmarking pluripotent stem cell-derived organoid models.

Cerebral organoids are stem cell-derived, self-organizing three-dimensional cultures. Owing to the remarkable degree to which they recreate the cellular diversity observed in the human brain, they have attracted significant interest as a novel model system for research and drug development, as well as capturing the public imagination. However, many questions remain about the extent to which these cultures recapitulate neurodevelopment and the defining features of the human brain.

Unraveling Mechanisms of Patient-Specific NRXN1 Mutations in Neuropsychiatric Diseases Using Human Induced Pluripotent Stem Cells.

Rare heterozygous deletions in the neurexin 1 (NRXN1) gene robustly increase an individual's risk of developing neurological and psychiatric disorders. However, the molecular bases by which different mutations result in different clinical presentations, with variable penetrance, are unknown. To better understand the molecular and cellular consequences of heterozygous NRXN1 mutations, Flaherty and colleagues studied how patient mutations influence the NRXN1 isoform repertoire and neuronal phenotypes using induced pluripotent stem (iPS) cells.

The Emerging Neurobiology of Bipolar Disorder.

(Reprinted with permission from , January 2018, Vol. 41, No. 1 ).

Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain.

RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline.

Correction: The genomic basis of mood instability: identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Which Dopamine Polymorphisms Are Functional? Systematic Review and Meta-analysis of COMT, DAT, DBH, DDC, DRD1-5, MAOA, MAOB, TH, VMAT1, and VMAT2.

Background: Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear.

It feels real: physiological responses to a stressful virtual reality environment and its impact on working memory.

Background: Virtual reality (VR) is increasingly used to study and treat psychiatric disorders. Its fidelity depends in part on the extent to which the VR environment provides a convincing simulation, for example whether a putatively stressful VR situation actually produces a stress response.

Methods: We studied the stress response in 28 healthy men exposed either to a stressor VR elevator (which simulated travelling up the outside of a tall building and culminated in the participant being asked to step off the elevator platform), or to a control elevator.

Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal.

We reappraise the psychiatric potential of calcium channel blockers (CCBs). First, voltage-gated calcium channels are risk genes for several disorders. Second, use of CCBs is associated with altered psychiatric risks and outcomes.

Dissociable Catecholaminergic Modulation of Visual Attention: Differential Effects of Catechol-O-Methyltransferase and Dopamine Beta-Hydroxylase Genes on Visual Attention.

Visual attention enables us to prioritise behaviourally relevant visual information while ignoring distraction. The neural networks supporting attention are modulated by two catecholamines, dopamine and noradrenaline. The current study investigated the effects of single nucleotide polymorphisms in two catecholaminergic genes - COMT (ValMet) and DBH (444 G/A) - on individual differences in attention functions.

The genomic basis of mood instability: identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function.

Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here, we report the results of a GWAS of mood instability as a trait in a large population cohort (UK Biobank, n = 363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways.