Biological effects of COMT haplotypes and psychosis risk in 22q11.2 deletion syndrome.

Background: 22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated with schizophrenia.

Use of postmortem human dura mater and scalp for deriving human fibroblast cultures.

Fibroblasts can be collected from deceased individuals, grown in culture, reprogrammed into induced pluripotent stem cells (iPSCs), and then differentiated into a multitude of cell types, including neurons. Past studies have generated iPSCs from somatic cell biopsies from either animal or human subjects. Previously, fibroblasts have only been successfully cultured from postmortem human skin in two studies.

Orientation and cellular distribution of membrane-bound catechol-O-methyltransferase in cortical neurons: implications for drug development.

Catechol-O-methyltransferase (COMT) is a key enzyme for inactivation and metabolism of catechols, including dopamine, norepinephrine, caffeine, and estrogens. It plays an important role in cognition, arousal, pain sensitivity, and stress reactivity in humans and in animal models. The human COMT gene is associated with a diverse spectrum of human behaviors and diseases from cognition and psychiatric disorders to chronic pain and cancer.

Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models.

Background: Neuregulin1 (NRG1)-ErbB signaling has been implicated in the pathogenesis of cancer and schizophrenia. We have previously reported that NRG1-stimulated migration of B lymphoblasts is PI3K-AKT1dependent and impaired in patients with schizophrenia and significantly linked to the catechol-o-methyltransferase (COMT) Val108/158Met functional polymorphism.

Methodology/principal Findings: We have now examined AKT1 activation in NRG1-stimulated B lymphoblasts and other cell models and explored a functional relationship between COMT and AKT1.

A haplotype containing quantitative trait loci for SLC1A1 gene expression and its association with obsessive-compulsive disorder.

Context: Recent evidence from linkage analyses and follow-up candidate gene studies supports the involvement of SLC1A1, which encodes the neuronal glutamate transporter, in the development of obsessive-compulsive disorder (OCD).

Objectives: To determine the role of genetic variation of SLC1A1 in OCD in a large case-control study and to better understand how SLC1A1 variation affects functionality.

Design: A case-control study.

How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems.

Discovered and crystallized over sixty years ago, serotonin's important functions in the brain and body were identified over the ensuing years by neurochemical, physiological and pharmacological investigations. This 2008 M. Rapport Memorial Serotonin Review focuses on some of the most recent discoveries involving serotonin that are based on genetic methodologies.

Refining psychiatric genetics: from 'mouse psychiatry' to understanding complex human disorders.

Investigating the pathogenesis of psychiatric disorders is a complicated and rigorous task for psychiatric geneticists, as the disorders often involve combinations of genetic, behavioral, personality, and environmental factors. To nurture further progress in this field, a new set of conceptual tools is needed in addition to the currently accepted approaches. Concepts that consider cross-species trait genetics and the interplay between the domains of disorders, as well as the full spectrum of potential symptoms and their place along the pathogenetic continuum, are particularly important to address these needs.

Domain interplay concept in animal models of neuropsychiatric disorders: a new strategy for high-throughput neurophenotyping research.

Genetic and environmental factors play a key role in psychiatric disorders. While some disorders display exceptionally high heritability, others show gene x experience x personality interactions, contributing complexity to psychiatric phenotypes. As some brain disorders frequently overlap and co-occur (representing a continuum or spectrum of phenomena), modern psychiatry is shifting from "artificial" heterogeneity to the recognition of common elements in the pathogenesis of emotional, personality and behavioral disorders.

A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a disabling neuropsychiatric illness with strong segregation data indicative of major genetic contributions. Association analyses of common functional variants of the serotonin transporter gene (SLC6A4), a long-standing OCD candidate, have so far been inconsistent. Here, we set out to investigate the role of additional functional SLC6A4 loci in OCD.

The developing use of heterozygous mutant mouse models in brain monoamine transporter research.

5-Hydroxytryptamine (5-HT), dopamine and norepinephrine are important monoamine neurotransmitters implicated in multiple brain mechanisms and regulated by high-affinity transmembrane monoamine transporters. Although knockout mice lacking 5-HT, dopamine or norepinephrine transporters are widely used to assess brain monoamine processes, these models have several methodological limitations. There is mounting evidence that heterozygous mutant mice with reduced (but not abolished) monoamine transporter functions could provide models with greater relevance to the genetics of human disorders, which only rarely involve complete loss-of-function mutations.

Gender-dependent modulation of brain monoamines and anxiety-like behaviors in mice with genetic serotonin transporter and BDNF deficiencies.

1. Brain-derived neurotrophic factor (BDNF) supports serotonergic neuronal development and our recent study found that heterozygous mice lacking one BDNF gene allele interbred with male serotonin transporter (SERT) knockout mice had greater reductions in brain tissue serotonin concentrations, greater increases in anxiety-like behaviors and greater ACTH responses to stress than found in the SERT knockout mice alone. 2.

Alternative splicing of human metabotropic glutamate receptor 3.

The metabotropic glutamate receptor 3 (GRM3, mGluR3) is important in regulating synaptic glutamate. Here, we report the existence of three splice variants of GRM3 in human brain arising from exon skipping events. The transcripts are expressed in prefrontal cortex, hippocampus and cerebellum, and in B lymphoblasts.

Serotonergic-like progenitor cells propagated from neural stem cells in vitro: survival with SERT protein expression following implantation into brains of mice lacking SERT.

Neural stem cells (NSCs) obtained from the midbrain region of embryonic (E14) mice were initially cultured with basic fibroblast growth factor (bFGF), Sonic hedgehog, and FGF-8 in a serum-free N-2 culture medium to foster differentiation into a serotonergic-like phenotype. During the initial differentiating phase, these progenitor cells expressed En1, Pax3, and Pax5 mRNA. Subsequently, a single serotonin [5-hydroxytryptamine (5-HT)] and tryptophan hydroxylase-positive clone was isolated, which gave rise to cells that developed serotonergic properties.

Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice.

To study the neurochemical and behavioral effects of altered brain-derived neurotrophic factor (BDNF) expression on a brain serotonin system with diminished serotonin transport capability, a double-mutant mouse model was developed by interbreeding serotonin transporter (SERT) knockout mice with BDNF heterozygous knockout mice (BDNF +/-), producing SERT -/- x BDNF +/- (sb) mice. Prior evidence implicates serotonin and SERT in anxiety and stress responses. Some studies have shown that BDNF supports serotonergic neuronal development, leading to our hypothesis that reduced BDNF availability during development might exaggerate the consequences of absent SERT function.