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.

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.

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.