The nanopeptide bradykinin is generated in stress conditions such as inflammation, trauma, burns, shock, and allergy. Receptor binding leads to an increase in the cytosolic calcium ion concentration, resulting in chronic and acute inflammatory responses. Not surprisingly, components of the kinin cascade display differential expression patterns in transcriptomic and proteomic surveys of multiple sclerosis inflammatory brain foci, and, as shown by Schulze-Topphoff and colleagues, also in the EAE CNS tissue and cerebrospinal fluid. Paradoxically, a kinin receptor B1 (Bdkrb1) agonist decreases the clinical expression of EAE, whereas the use of an antagonist resulted in earlier onset and increase severity. Similarly, EAE induction in the Bdkrb1-deficient mice resulted in more severe disease and increased inflammatory infiltrates. Bdkrb1 is expressed in both parenchymal CD3+ T cells within the perivascular lesions and on brain endothelial cells, and a series of in vitro experiments suggest a pivotal role for the receptor in modulating the migration of Th17 inflammatory cells across the blood brain barrier. The authors predict that novel kinin receptor agonists developed primarily for cardiovascular diseases, will find application in the treatment of multiple sclerosis and other autoimmune and chronic inflammatory disorders (Nature Medicine 2009 In press; PMID: 19561616).
Chromatin remodeling in neuroadaptation to cocaine
Much evidence supports the hypothesis that repeated exposure to abused drugs produces changes in gene expression, which lead to neuroadaptations that foster addiction. Analyses of mRNA transcripts in limbic brain regions that mediate drug reward have revealed candidate genes that participate in these neuroadaptations. However, gene array studies only measure steady-state levels of transcripts, which may not reflect changes in transcriptional regulation of genes. Here Renthal and colleagues instead performed a genome-wide analysis of chromatin remodeling using chromatin immunoprecipitation followed by promoter microarray analysis (ChIP-chip) with antibodies against acetylated and methylated histones, and against phospho-CREB and delta-FosB, which are two transcription factors strongly implicated in adaptive responses to cocaine. Mice were injected daily with 20 mg/kg cocaine for 7 days and then samples of the nucleus accumbens, a brain region critical for drug reward, were analyzed for chromatin remodeling and transcription factor binding. Proximal promoter regions of several genes previously shown to be induced by cocaine showed increased binding of acetylated H3 or H4 histone. Conversely, genes known to be suppressed by cocaine generally showed increases in histone methylation. The technique also revealed several genes known to be regulated by delta-FosB and phosphorylated CREB. Of interest were several genes not known previously to be regulated by cocaine. For example, the analysis suggested that cocaine increases expression of the sirtuins SIRT1 and SIRT2, which are histone deacetylases that play key roles in metabolism and aging and are of interest as drug targets. Increasing sirtuin activity increased the firing of nucleus accumbens medium spiny neurons and promoted cocaine reward, whereas inhibiting sirtuin activity reduced neuronal firing, reduced cocaine reward and decreased cocaine self-administration. These results show that simultaneous analysis of chromatin remodeling and gene expression can reveal novel disease mechanisms and therapeutic targets for treatment of addiction. (Neuron. 2009, 62:335-48; PMID: 19447090)
VEGF: not just for angiogenesis
Much attention has been paid to the role of VEGF and its ligands in angiogenesis in the developing and mature nervous system. More recently, however, the role of VEGF and its receptors in neurogenesis is becoming apparent. Using a domain-specific knock-out mouse lacking the VEGFR-1 intracellular domain (Flt-1TK_/_) these investigators show unique functions for vascular endothelial growth factor receptor-1 (VEGFR-1) in adult olfactory neurogenesis. They compared neural progenitor cell proliferation, migration, and differentiation from wild-type and VEGFR-1 signaling-deficient mice (Flt-1TK-/- mice). VEGFR-1 is expressed in GFAP+ cells in neurogenic regions. VEGFR-1 signaling appears to negatively regulate proliferation of adult neuronal progenitor cells within the subventricular zone (SVZ), promotes migration along the rostral migratory stream (RMS), and results in neuronal differentiation and phenotype of interneuron subtypes within the olfactory bulb. Migration along the RMS is altered in the knockouts mainly as a result of increased levels of VEGF-A, which results in an increased phosphorylation of VEGFR-2 in neuronal progenitor cells within the SVZ and the RMS. These effects are seen without vascular changes in these regions and provide additional data on how VEGF signaling contributes to neurogenesis in the adult brain (J Neurosci 2009; 29:8704–8714; PMID: 19587277)
Common polymorphisms, the MHC, and schizophrenia
Schizophrenia is a prevalent psychiatric disorder (0.5-1%) with high (80-85%) but complex heritability. Recent multi-center studies in large sample collections confirmed the relative high frequency of de-novo, highly penetrant rare DNA copy number variants in individuals affected with schizophrenia, but the role of common single nucleotide polymorphism (SNPs) in this disease remains unclear. Three consecutive papers report on the use of last generation SNP arrays with dense genome-wide coverage to genotype multiple case-control datasets of European ancestry and a smaller African-American one. Altogether, the data and partial pooled analysis of the different studies are consistent with the presence of multiple susceptibility genes of modest effect, the MHC region in chromosome 6p21 being the most prominent and reproducible. This 4 Mb region is gene-rich but best known for the presence of HLA genes involved in the immune response and susceptibility to autoimmune diseases. The failure to identify a specific HLA allele or haplotype associated with the disease suggests that linking schizophrenia with autoimmunity may be premature. Indeed, one of the studies mapped the association signal just outside, telomeric to the classical MHC region, in a chromosomal region that also includes immunity related genes, but also a histone gene cluster. Authors in one of the studies modeled the data using very liberal thresholds of significance, and suggested that thousands of common variants contribute to susceptibility. This extreme polygenic model may be also applicable to bipolar disease (Nature In press PMID 19571809, 19571811, 19571808).
Filed under: Discoveries in Neuroscience | Tagged: allergy, Bdkrb1, burns, CD3+ T, cerebrospinal fluid, chronic and acute inflammatory responses, cytosolic calcium, EAE CNS tissue, inflammation, nanopeptide bradykinin, shock, trauma
