Evidence of a pathogenic role for CD8(+) T cells in anti-GABAB receptor limbic encephalitis.

Objectives: To characterize the cellular autoimmune response in patients with γ-aminobutyric acid (GABA)B receptor antibody-associated limbic encephalitis (GABAB-R LE).

Methods: Patients underwent MRI, extensive neuropsychological assessment, and multiparameter flow cytometry of peripheral blood and CSF.

Results: We identified a series of 3 cases of nonparaneoplastic GABAB-R LE and one case of paraneoplastic GABAB-R LE associated with small cell lung cancer.

Identification of Synaptotagmin 10 as Effector of NPAS4-Mediated Protection from Excitotoxic Neurodegeneration.

Unlabelled: Neuronal degeneration represents a pathogenetic hallmark after different brain insults, such as ischemia and status epilepticus (SE). Excessive release of glutamate triggered by pathophysiologic synaptic activity has been put forward as key mechanism in this context. In response to pathophysiologic synaptic activity, multiple signaling cascades are activated that ultimately initiate expression of specific sets of genes, which may decide between neuronal survival versus death.

Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1.

Temporal lobe epilepsy (TLE) is the most common focal seizure disorder in adults. In many patients, transient brain insults, including status epilepticus (SE), are followed by a latent period of epileptogenesis, preceding the emergence of clinical seizures. In experimental animals, transcriptional upregulation of CaV3.

Molecular imaging reveals epileptogenic Ca2+-channel promoter activation in hippocampi of living mice.

Focal epilepsies often originate in the hippocampal formation of the temporal lobe (temporal lobe epilepsy) and are generally acquired after transient brain insults. Such insults induce cellular and structural reorganization processes of the hippocampus, referred to as epileptogenesis that finally convert the brain spontaneous epileptic. Here, we developed a new molecular imaging strategy in a state-of-the-art animal model to provide insights into key epileptogenic mechanisms.

Rs6295 promoter variants of the serotonin type 1A receptor are differentially activated by c-Jun in vitro and correlate to transcript levels in human epileptic brain tissue.

Many brain disorders, including epilepsy, migraine and depression, manifest with episodic symptoms that may last for various time intervals. Transient alterations of neuronal function such as related to serotonin homeostasis generally underlie this phenomenon. Several nucleotide polymorphisms (SNPs) in gene promoters associated with these diseases have been described.

Zinc induces long-term upregulation of T-type calcium current in hippocampal neurons in vivo.

Extracellular zinc can induce numerous acute and persistent physiological and toxic effects in neurons by acting at their plasma membrane or intracellularly following permeation or uptake into them. Zinc acutely and reversibly blocks T-type voltage-gated calcium current (I(CaT)), but the long-term effect of zinc on this current has not been studied. Because chemically induced status epilepticus (SE) results in the release of zinc into the extracellular space, as well as in a long-lasting increase in I(CaT) in CA1 pyramidal cells, we hypothesized that zinc may play a causative role in I(CaT) upregulation.

Transcriptional regulation of T-type calcium channel CaV3.2: bi-directionality by early growth response 1 (Egr1) and repressor element 1 (RE-1) protein-silencing transcription factor (REST).

The pore-forming Ca(2+) channel subunit Ca(V)3.2 mediates a low voltage-activated (T-type) Ca(2+) current (I(CaT)) that contributes pivotally to neuronal and cardiac pacemaker activity. Despite the importance of tightly regulated Ca(V)3.

Promoter variants determine γ-aminobutyric acid homeostasis-related gene transcription in human epileptic hippocampi.

The functional consequences of single nucleotide polymorphisms associated with episodic brain disorders such as epilepsy and depression are unclear. Allelic associations with generalized epilepsies have been reported for single nucleotide polymorphisms rs1883415 (ALDH5A1; succinic semialdehyde dehydrogenase) and rs4906902 (GABRB3; GABAA β3), both of which are present in the 5' regulatory region of genes involved in γ-aminobutyric acid (GABA) homeostasis. To address their allelic association with episodic brain disorders and allele-specific impact on the transcriptional regulation of these genes in human brain tissue, DNA and messenger RNA (mRNA) isolated from hippocampi were obtained at epilepsy surgery of 146 pharmacoresistant mesial temporal lobe epilepsy (mTLE) patients and from 651 healthy controls.

Dual association of a TRKA polymorphism with schizophrenia.

Objective: An interaction between predisposing genes and environmental stressors is thought to underlie the neurodevelopmental disorder schizophrenia. In a targeted gene screening, we previously found that the minor allele of the single nucleotide polymorphism (SNP) rs6336 in the neurotrophic tyrosine kinase receptor 1 (NTRK1/TRKA) gene is associated with schizophrenia as a risk factor.

Methods: We genotyped the TRKA SNP in a total of eight independent Caucasian schizophrenia case-control groups.

Clock genes and body composition in patients with schizophrenia under treatment with antipsychotic drugs.

Context: In the healthy population, several pathways are known to exert an effect on basal metabolic factors. Previous studies have found associations between single nucleotide polymorphisms in clock genes or downstream hormone receptors such as the leptin receptor (LEPR) or glucocorticoid receptor (NR3C1) and obesity in the healthy population, but this association remains to be examined in patients with schizophrenia treated with antipsychotics.

Objective: To assess anthropomorphic parameters in patients taking second-generation antipsychotics (SGA) as a function of nine polymorphisms in three core genes of the clock pathway, and two genes of downstream hormone receptors.

Dopamine susceptibility of APO-SUS rats is not per se coupled to HPA-axis activity.

A synergistic relationship is thought to exist between hypothalamic-pituitary-adrenal (HPA) axis activity and dopamine neurotransmission. To test whether a high response to dopamine indeed implies a hyperactive HPA-axis, we here used Wistar rats that were selected twice independently (original and replicate lines) for a high or low susceptibility to the dopamine receptor agonist apomorphine (so-called APO-SUS and APO-UNSUS rats, respectively). The APO-SUS rats from the original line displayed a hyperactive HPA-axis in that higher basal and stress-induced adrenocorticotropic hormone (ACTH) levels, and lower basal free-corticosterone levels were observed than those found in the original APO-UNSUS rats.

Gene expression profiling in brain regions of a rat model displaying schizophrenia-related features.

Animal models allow insights into complex neurodevelopmental disorders. Apomorphine-susceptible rats (so-called APO-SUS rats) provide a model that displays a complex phenotype with schizophrenia-related features and together with its phenotypic counterpart (APO-UNSUS rats) has been independently generated twice (original and replicate rat lines). To understand the molecular basis underlying this phenotype, we here performed mRNA expression profiling in various APO-SUS and APO-UNSUS rat brain regions.

Correlation between HIV-1 seropositivity and prevalence of a gamma-secretase polymorphism in two distinct ethnic populations.

Susceptibility for human immunodeficiency virus type 1 (HIV-1) infection may be influenced by host genetics. Recent findings with a Wistar rat model raised the possibility that the gamma-secretase pathway may be associated with an individual's susceptibility to infection. A functional single-nucleotide polymorphism (SNP) in the gamma-secretase component APH1B (Phe217Leu; rs1047552) was therefore analyzed for association with HIV-1 infection.

Three-cohort targeted gene screening reveals a non-synonymous TRKA polymorphism associated with schizophrenia.

Schizophrenia is a complex neurodevelopmental disorder that is thought to be induced by an interaction between predisposing genes and environmental stressors. To identify predisposing genetic factors, we performed a targeted (mostly neurodevelopmental) gene approach involving the screening of 396 selected non-synonymous single-nucleotide polymorphisms (SNPs) in three independent Caucasian schizophrenia case-control cohorts (USA, Denmark and Norway). A meta-analysis revealed ten non-synonymous SNPs that were nominally associated with schizophrenia, nine of which have not been previously linked to the disorder.

Male-specific association between a gamma-secretase polymorphism and premature coronary atherosclerosis.

Background: Atherosclerosis is a common multifactorial disease resulting from an interaction between susceptibility genes and environmental factors. The causative genes that contribute to atherosclerosis are elusive. Based on recent findings with a Wistar rat model, we speculated that the gamma-secretase pathway may be associated with atherosclerosis.

Rats that differentially respond to cocaine differ in their dopaminergic storage capacity of the nucleus accumbens.

Cocaine (COC) inhibits the re-uptake of dopamine. However, the dopamine response to COC also depends on dopamine inside storage vesicles. The aim of this study was to investigate whether rats that differentially respond to COC differ in their dopaminergic storage capacity of the nucleus accumbens.

Identification of genetic and epigenetic variations in a rat model for neurodevelopmental disorders.

A combination of genetic variations, epimutations and environmental factors may be involved in the etiology of complex neurodevelopmental disorders like schizophrenia. To study such disorders, we use apomorphine-unsusceptible (APO-UNSUS) Wistar rats and their phenotypic counterpart apomorphine-susceptible (APO-SUS) rats that display a complex phenotype remarkably similar to that of schizophrenic patients. As the molecular basis of the APO-SUS/UNSUS rat model, we recently identified a genomic rearrangement of the Aph-1b gene.

Reduced Aph-1b expression causes tissue- and substrate-specific changes in gamma-secretase activity in rats with a complex phenotype.

The gamma-secretase enzyme complex displays intramembrane catalytic activity toward many type I transmembrane proteins, including the Alzheimer-linked amyloid-beta-protein precursor (APP) and the neuregulin receptor ErbB4. Active gamma-secretase is a tetrameric protein complex consisting of presenilin-1 (or -2), nicastrin, PEN-2, and Aph-1a (or -1b). We have recently discovered that pharmacogenetically bred apomorphine-susceptible Wistar rats (APO-SUS) have only one or two copies of the Aph-1b gene (termed I/I and II/II rats, respectively), whereas their phenotypic counterparts (APO-UNSUS) have three copies (III/III).

Gene dosage effect on gamma-secretase component Aph-1b in a rat model for neurodevelopmental disorders.

A combination of genetic factors and early life events is thought to determine the vulnerability of an individual to develop a complex neurodevelopmental disorder like schizophrenia. Pharmacogenetically selected, apomorphine-susceptible Wistar rats (APO-SUS) display a number of behavioral and pathophysiological features reminiscent of such disorders. Here, we report microarray analyses revealing in APO-SUS rats, relative to their counterpart APO-UNSUS rats, a reduced expression of Aph-1b, a component of the gamma-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways.