Britta Haenisch

Genome-Wide Association-, Replication-, and Neuroimaging Study Implicates HOMER1 in the Etiology of Major Depression

BACKGROUND Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression. METHODS We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects. RESULTS Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 (p(combined) = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (p(combined) = 1.48E-6), located in a putative regulatory region of HOMER1. Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 (p(combined) = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consistent with the findings of our subsequent human imaging genetics study, which revealed that variation in single nucleotide polymorphism rs7713917 had a significant influence on prefrontal activity during executive cognition and anticipation of reward. CONCLUSION Our findings, combined with evidence from preclinical and animal studies, suggest that HOMER1 plays a role in the etiology of major depression and that the genetic variation affects depression via the dysregulation of cognitive and motivational processes.

Depression and antidepressants: Insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters

Major depressive disorder (MDD) which is supposed to result from a complex interaction of genetic and epigenetic, environmental and developmental factors is one of the most common debilitating public health problems. The molecular mechanisms underlying this disease are still largely unclear. Identifying common pathways for diverse antidepressants (ADs) as well as new drug targets and thereby developing more effective treatments are primary goals of research in this field. Major targets of ADs are the serotonin transporter (SERT), the noradrenaline transporter (NAT) and also the dopamine transporter (DAT) located in the plasma membrane of corresponding neurons. These monoamine transporters (MATs) are important regulators of the extracellular neurotransmitter concentration. Among the clinically important ADs are tricyclic ADs (e.g. imipramine), selective serotonin re-uptake inhibitors (SSRIs, e.g. fluoxetine), selective noradrenaline (NA) re-uptake inhibitors (SNRIs, e.g. reboxetine) and NAT/DAT inhibitors like bupropion. This review is focussing on brain changes in monoamine neurotransmitter systems, downstream targets of monoaminergic neurotransmission as well as of behaviours of mice with a conventional knockout (KO) of either the SERT, DAT or NAT. MAT knockout induces changes in behaviour and brain neurochemistry. Although at least NATKO and SERTKO mice were expected to show a phenotype like AD-treated wild-type mice, this holds true only for the NATKO mice whereas SERTKO mice show an anxiety-like phenotype. Chronic social or restraint stress-induced depression-like behaviour and concomitant changes in brain neurotrophins are prevented by pharmacologically diverse ADs and by NATKO. Thus, NATKO mice are an interesting tool to investigate the mechanisms beyond monoamines responsible for depression as well as for AD actions.

Structure―activity relationships of flavonoids as inhibitors of breast cancer resistance protein (BCRP)

Flavonoids are an interesting group of natural products ubiquitously present in human diet. Their consumption has been associated with various and differing beneficial health effects. However, several flavonoids have been reported to inhibit the breast cancer resistance protein (BCRP) encoded by the ABCG2 gene. Thus, the consumption of flavonoids with high inhibitory activity could change pharmacokinetics and drug levels of drugs that are BCRP substrates. In cancer patients receiving chemotherapy an increased intake of such flavonoids could lead to adverse effects. We investigated a structurally diverse set of flavonoids, including derivatives with a rare C-methylated structure that were isolated from plants used in traditional medicine. The flavones retusin and ayanin were found to be highly potent inhibitors of BCRP, showing only slightly less potency than Ko143, the most potent ABCG2 inhibitor known so far. The activity data were analyzed by 2D and 3D QSAR analyses and the results revealed the impact of the different substituents at the various positions of the flavonoid core on activity. Additionally, a lateral 2D QSAR analysis of data collected from the literature was performed aiming to derive more general information about the influence of distinct structural features on the inhibitory potency of flavonoids. The comparative QSAR analyses led to a consistent picture of the effects of the different substituents at various positions of the flavone backbone. The following structural features were found to contribute positively to BCRP inhibition: a hydroxyl group in position 5, double bond between position 2 and 3, and a methoxy group in position 3. The exchange of a 3-methoxy group by an OH-group acting also as a hydrogen bond donor, resulted in decrease in activity underlining the potential role of the hydrogen bond acceptor 3-OCH(3) for the interaction with BCRP.

Agmatine: clinical applications after 100 years in translation.

Agmatine (decarboxylated arginine) has been known as a natural product for over 100 years, but its biosynthesis in humans was left unexplored owing to long-standing controversy. Only recently has the demonstration of agmatine biosynthesis in mammals revived research, indicating its exceptional modulatory action at multiple molecular targets, including neurotransmitter systems, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for broad therapeutic applications. This timely review, a concerted effort by 16 independent research groups, draws attention to the substantial preclinical and initial clinical evidence, and highlights challenges and opportunities, for the use of agmatine in treating a spectrum of complex diseases with unmet therapeutic needs, including diabetes mellitus, neurotrauma and neurodegenerative diseases, opioid addiction, mood disorders, cognitive disorders and cancer.

Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression

Diverse factors such as changes in neurotrophins and brain plasticity have been proposed to be involved in the actions of antidepressant drugs (ADs). However, in mouse models of depression based on chronic stress, it is still unclear whether simultaneous changes in behavior and neurotrophin expression occur and whether these changes can be corrected or prevented comparably by chronic administration of ADs or genetic manipulations that produce antidepressant‐like effects such as the knockout of the norepinephrine transporter (NET) gene. Here we show that chronic restraint or social defeat stress induce comparable effects on behavior and changes in the expression of neurotrophins in depression‐related brain regions. Chronic stress caused down‐regulation of BDNF, nerve growth factor, and neurotrophin‐3 in hippocampus and cerebral cortex and up‐regulation of these targets in striatal regions. In wild‐type mice, these effects could be prevented by concomitant chronic administration of five pharmacologically diverse ADs. In contrast, NET knock out (NETKO) mice were resistant to stress‐induced depressive‐like changes in behavior and brain neurotrophin expression. Thus, the resistance of the NETKO mice to the stress‐induced depression‐associated behaviors and biochemical changes highlight the importance of noradrenergic pathways in the maintenance of mood. In addition, these mice represent a useful model to study depression‐resistant behaviors, and they might help to provide deeper insights into the identification of downstream targets involved in the mechanisms of antidepressants.

Agmatine (decarboxylated L-arginine): physiological role and therapeutic potential.

Agmatine, a cationic amine formed by decarboxylation of l-arginine by the mitochondrial enzyme arginine decarboxylase (ADC), is widely but unevenly distributed in mammalian tissues. Agmatine in the tissues originates from cellular enzymatic de novo synthesis and from agmatine absorbed from the lumen of the gut. Absorption from the gut and accumulation in the tissues and cells must occur via a specific carrier mechanism because the compound is charged at physiologic pH and, hence, biological membranes are almost completely impermeable to the organic cation in the absence of an uptake system. Agmatine initially attracted attention as an endogenous ligand at imidazoline receptors and α(2)-adrenoceptors. However, independent of binding to those receptors, agmatine induces a variety of physiological and pharmacological effects exhibiting a great therapeutic potential of the compound. Although the precise function of endogenous agmatine is presently still unclear, this review summarizes the current knowledge concerning the physiological and pathophysiological function of agmatine.

Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder.

We used genome-wide single nucleotide polymorphism (SNP) data to search for the presence of copy number variants (CNVs) in 882 patients with bipolar disorder (BD) and 872 population-based controls. A total of 291 (33%) patients had an early age-at-onset ⩽21 years (AO⩽21years). We systematically filtered for CNVs that cover at least 30 consecutive SNPs and which directly affect at least one RefSeq gene. We tested whether (a) the genome-wide burden of these filtered CNVs differed between patients and controls and whether (b) the frequency of specific CNVs differed between patients and controls. Genome-wide burden analyses revealed that the frequency and size of CNVs did not differ substantially between the total samples of BD patients and controls. However, separate analysis of patients with AO⩽21years and AO>21years showed that the frequency of microduplications was significantly higher (P=0.0004) and the average size of singleton microdeletions was significantly larger (P=0.0056) in patients with AO⩽21years compared with controls. A search for specific BD-associated CNVs identified two common CNVs: (a) a 160 kb microduplication on 10q11 was overrepresented in AO⩽21years patients (9.62%) compared with controls (3.67%, P=0.0005) and (b) a 248 kb microduplication on 6q27 was overrepresented in the AO⩽21years subgroup (5.84%) compared with controls (2.52%, P=0.0039). These data suggest that CNVs have an influence on the development of early-onset, but not later-onset BD. Our study provides further support for previous hypotheses of an etiological difference between early-onset and later-onset BD.

Familial Occurrence of Systemic Mast Cell Activation Disease

Systemic mast cell activation disease (MCAD) comprises disorders characterized by an enhanced release of mast cell mediators accompanied by accumulation of dysfunctional mast cells. Demonstration of familial clustering would be an important step towards defining the genetic contribution to the risk of systemic MCAD. The present study aimed to quantify familial aggregation for MCAD and to investigate the variability of clinical and molecular findings (e.g. somatic mutations in KIT) among affected family members in three selected pedigrees. Our data suggest that systemic MCAD pedigrees include more systemic MCAD cases than would be expected by chance, i.e., compared with the prevalence of MCAD in the general population. The prevalence of MCAD suspected by symptom self-report in first-degree relatives of patients with MCAD amounted to approximately 46%, compared to prevalence in the general German population of about 17% (p<0.0001). In three families with a high familial loading of MCAD, the subtype of MCAD and the severity of mediator-related symptoms varied between family members. In addition, genetic alterations detected in KIT were variable, and included mutations at position 816 of the amino acid sequence. In conclusion, our data provide evidence for common familial occurrence of MCAD. Our findings observed in the three pedigrees together with recent reports in the literature suggest that, in familial cases (i.e., in the majority of MCAD), mutated disease-related operator and/or regulator genes could be responsible for the development of somatic mutations in KIT and other proteins important for the regulation of mast cell activity. Accordingly, the immunohistochemically different subtypes of MCAD (i.e. mast cell activation syndrome and systemic mastocytosis) should be more accurately regarded as varying presentations of a common generic root process of mast cell dysfunction, than as distinct diseases.

Association of major depression with rare functional variants in norepinephrine transporter and serotonin1A receptor genes.

Dysregulations of central noradrenergic and serotonergic neurotransmission have been suggested to contribute to the pathogenesis of neuropsychiatric disorders such as depression. The norepinephrine transporter (NET; SLC6A2) and the serotonin (5‐HT)1A receptor (5‐HT1A receptor; HTR1A) play an important role in central nervous monoaminergic homeostasis. As shown previously, variations in the human NET and 5‐HT1A receptor genes can alter noradrenergic and serotonergic signaling in the brain: a single nucleotide polymorphism (SNP) in the coding region of the NET gene resulting in a F528C substitution increased plasma membrane expression of this NET variant, and a SNP in the human 5‐HT1A receptor gene leading to the R219L receptor variant almost abolished cellular signal transduction subsequent to receptor activation. The present study aimed at investigating whether these NET and 5‐HT1A receptor variants are associated with major depression (MD). The sample comprised 426 patients suffering from unipolar MD as well as 643 healthy control subjects for the variants of the 5‐HT1A receptor and the NET. Both SNPs were shown to be associated with MD. In conclusion, our results favor the hypothesis that monoaminergic neurotransmission in general and the F528C NET and R219L 5‐HT1A receptor variants in particular are involved in the pathogenesis of depression.

Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics

Despite increasing understanding of its pathophysiology, the aetiology of systemic mast cell activation disease (MCAD) remains largely unknown. Research has shown that somatic mutations in kinases are necessary for the establishment of a clonal mast cell population, in particular mutations in the tyrosine kinase Kit and in enzymes and receptors with crucial involvement in the regulation of mast cell activity. However, other, as yet undetermined, abnormalities are necessary for the manifestation of clinical disease. The present article reviews molecular genetic research into the identification of disease‐associated genes and their mutational alterations. The authors also present novel data on familial systemic MCAD and review the associated literature. Finally, the importance of understanding the molecular basis of inherited mutations in terms of diagnostics and therapy is emphasized.