The novel brain-specific tryptophan hydroxylase-2 gene in panic disorder.

Panic disorder is a common psychiatric disorder characterized by recurrent anxiety attacks and anticipatory anxiety. Due to the severity of the symptoms of the panic attacks and the frequent additional occurrence of agoraphobia, panic disorder is an often debilitating disease. Elevation of central serotonin levels by drugs such as clomipramine represents one of the most effective treatment options for panic disorder. This points to an important role of dysregulation of the serotonergic system in the genetic etiology of panic disorder. The novel brain-specific 5-HT synthesizing enzyme, tryptophan hydroxylase-2 (TPH2), which represents the rate-limiting enzyme of 5-HT production in the brain, may therefore be of particular importance in panic disorder. We focused on the putative transcriptional control region of TPH2 and identified two novel common single nucleotide polymorphisms (SNPs) of TPH2 in and close to this region. Moreover, a recently described loss-of-function mutation of TPH2 which results in an 80% reduction of serotonin production, was assessed. In an analysis of the putative transcriptional control region SNPs in a sample of panic disorder patients and controls no association of the disorder with the TPH2 SNPs or haplotypes was found. Moreover, the loss-of-function R441H mutation of TPH2 was not present in the panic disorder patients. The results of this first study of TPH2 in panic disorder argue against an importance of allelic variation of TPH2 in the pathogenesis of panic disorder with or without agoraphobia.

Synaptotagmin I and IV are differentially regulated in the brain by the recreational drug 3,4-methylenedioxymethamphetamine (MDMA).

3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) is a widely abused drug. In brains of mice exposed to MDMA, we recently detected altered expression of several cDNAs and genes by using the differential display polymerase chain reaction (PCR) method. Expression of one such cDNA, which exhibited 98% sequence homology with the synaptic vesicle protein synaptotagmin IV, decreased 2 h after MDMA treatment. Herein, the effect of MDMA on expression of both synaptotagmin I and IV was studied in detail, since the two proteins are functionally interrelated. PCR analyses (semi-quantitative and real-time) confirmed that upon treatment with MDMA, expression of synaptotagmin IV decreased both in the midbrain and frontal cortex of mice. Decreases in the protein levels of synaptotagmin IV were confirmed by Western immunoblotting with anti-synaptotagmin IV antibodies. In contrast, the same exposure to MDMA increased expression of synaptotagmin I in the midbrain, a region rich in serotonergic neurons, but not in the frontal cortex. This differential expression was confirmed at the protein level with anti-synaptotagmin I antibodies. MDMA did not induce down- or up-regulation of synaptotagmin IV and I, respectively, in serotonin transporter knockout mice (-/-) that are not sensitive to MDMA. Therefore, psychoactive drugs, such as MDMA, appear to modulate expression of synaptic vesicle proteins, and possibly vesicle trafficking, in the brain.

Knockout mice in neuropsychopharmacology: present and future.

The technique of targeted inactivation of individual genes in mice has undoubtedly revolutionized biomedicine. Applications for gene knockout mice in neuropsychopharmacology are manifold: Determination of targets for established treatments is eased, while development of novel drugs is facilitated for a given target. This review discusses advantages and limitations of gene knockout strategies and, in particular, their relevance for the development of novel diagnostic and therapeutic approaches in psychiatric disorders. In addition to the classical targeted disruption of one or several genes simultanously, it specifically emphasizes those novel techniques that allow the inactivation of a gene with spatio-temporal selectivity.

Serotonin transporter promoter polymorphism influences topography of inhibitory motor control.

The prefrontal cortex participates in motor control and is modulated by serotonergic activity. The serotonin transporter (5-HTT) is a major regulator of serotonergic neurotransmission and may thus influence motor control. The short allele (s) of the 5-HTT linked polymorphic region (5-HTTLPR) is associated with less 5-HTT expression and function than the long variant (l). The neurophysiological parameters termed 'Go- and NoGo- centroid location' represent characteristic brain electrical substrates of the execution and inhibition of motor response elicited by the Continuous Performance Test (CPT). In the present study, the impact of the 5-HTTLPR genotype on the centroid locations was investigated in 23 healthy subjects. The NoGo-centroid, but not the Go-centroid, was located significantly more anteriorly in the short allele group (mean electrode location in s/s and s/l, 2.86+/-0.37) compared to the group with two long alleles (l/l, 3.34+/-0.49; t=2.66, p<0.05). Age, gender, and test performance did not differ between groups. The results indicate that 5-HTTLPR genotype dependent 5-HTT function is associated with the neurophysiologically assessed topography of inhibitory motor control and provides further evidence for a genetic influence on central serotonergic and motor function.

A novel BDNF polymorphism affects plasma protein levels in interaction with early adversity in rhesus macaques.

Early stressful events can increase vulnerability for psychopathology, although knowledge on the effectors is still limited. In this report we describe the characterization of a single nucleotide polymorphism (SNP) in rhesus macaques, which results in a Val to Met transition in the pro-BDNF domain, similar to a well described variant in the human gene. Further, we tested the hypothesis that peripheral levels of BDNF, which is involved in the response to stress and in the pathophysiology of anxiety and depression, might be differentially affected in a non-human primate model of early adverse rearing in a genotype-dependent manner. Males and females rhesus macaques reared either with their mothers (MR), in peer-only groups (PR), or in a "surrogate/peer-reared" (SPR) condition with limited peer interactions, were used as experimental subjects. BDNF levels were determined at baseline on postnatal days (PND) 14, 30 and 60 by means of specific ELISA procedure. Data indicate that BDNF levels were increased as a result of peer-rearing and that this increase was moderated by the presence of the SNP. Overall these data indicate that a SNP, which results in a Val to Met transition in the pro-BDNF domain, is present in rhesus macaques and is able to affect BDNF peripheral levels, thus making this primate model a fundamental tool to study gene by environment interactions involving the BDNF gene.