http://www.molecularbrain.com The latest research articles published by Molecular Brain 2010-09-05T00:00:00Z This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ New granule cells are continuously generated in the dentate gyrus of the adult hippocampus. During granule cell maturation, the mechanisms that differentiate new cells not only describe the degree of cell differentiation, but also crucially regulate the progression of cell differentiation. Here, we describe a gene, tryptophan 2,3-dioxygenase (TDO), whose expression distinguishes stem cells from more differentiated cells among the granule cells of the adult mouse dentate gyrus. The use of markers for proliferation, neural progenitors, and immature and mature granule cells indicated that TDO was expressed in mature cells and in some immature cells. In mice heterozygous for the alpha-isoform of calcium/calmodulin-dependent protein kinase II, in which dentate gyrus granule cells fail to mature normally, TDO immunoreactivity was substantially downregulated in the dentate gyrus granule cells. Moreover, a 5-bromo-2'-deoxyuridine labeling experiment revealed that new neurons began to express TDO between 2 and 4 wk after the neurons were generated, when the axons and dendrites of the granule cells developed and synaptogenesis occurred. These findings indicate that TDO might be required at a late-stage of granule cell development, such as during axonal and dendritic growth, synaptogenesis and its maturation. http://www.molecularbrain.com/content/3/1/26 Koji Ohira Hideo Hagihara Keiko Toyama Keizo Takao Masaaki Kanai Hiroshi Funakoshi Toshikazu Nakamura Tsuyoshi MIyakawa Molecular Brain 2010, 3:26 2010-09-05T00:00:00Z doi:10.1186/1756-6606-3-26 Molecular Brain 1756-6606 3 26 2010-09-05T00:00:00Z PDF Background: All antipsychotic work via dopamine D2 receptors (D2Rs), suggesting a critical role for D2Rs in psychosis; however, there is little evidence for a change in receptor number or pharmacological nature of D2Rs. Recent data suggest that D2Rs form dimers in-vitro and in-vivo, and we hypothesized that schizophrenia, as well as preclinical models of schizophrenia, would demonstrate altered dimerization of D2Rs, even though the overall number of D2Rs was unaltered. Methods: We measured the expression of D2Rs dimers and monomers in patients with schizophrenia using Western blots, and then in striatal tissue from rats exhibiting the amphetamine-induced sensitized-state (AISS). We then examined the interaction between D2Rs and the dopamine transporter (DAT) by co-immunoprecipitation, and measured the expression of dopamine D2High receptors with ligand binding assays in rat striatum slices with and without acute amphetamine pre-treatment. Results: We observed significantly enhanced expression of D2Rs dimers (277.7+/-33.6%) and decreased expression of D2Rs monomers in post-mortem striatal tissue of schizophrenia patients. We found that amphetamine facilitated D2Rs dimerization in both the striatum of AISS rats and in rat striatal neurons. Furthermore, amphetamine-induced D2Rs dimerization may be associated with the D2R-DAT protein-protein interaction as an interfering peptide that disrupts the D2R-DAT coupling, blocked amphetamine-induced upregulation of D2Rs dimerization. Conclusions: Given the fact that amphetamine induces psychosis and that the AISS rat is a widely accepted animal model of psychosis, our data suggest that D2R dimerization may be important in the pathophysiology of schizophrenia and may be a promising new target for novel antipsychotic drugs. http://www.molecularbrain.com/content/3/1/25 Min Wang Lin Pei Paul Fletcher Shitij Kapur Philip Seeman Fang Liu Molecular Brain 2010, 3:25 2010-09-02T00:00:00Z doi:10.1186/1756-6606-3-25 Molecular Brain 1756-6606 3 25 2010-09-02T00:00:00Z PDF Background: Memory is the ability to store, retain, and later retrieve information that has been learned. Intermediate term memory (ITM) that persists for up to 3h requires new protein synthesis. Long term memory (LTM) that persists for at least 24h requires: DNA transcription, RNA translation, and the trafficking of newly synthesized proteins. It has been shown in a number of different model systems that NMDA receptors, protein kinase C (PKC) and mitogen activated protein kinase (MAPK) are all involved in the memory formation process. Results: Here we show that snails trained in control conditions are capable of forming, depending on the training procedure used, either ITM or LTM. However, blockage of NMDA receptors (MK 801), inhibition of PKC (GF109203X hydrochloride) and MAPK activity (UO126) prevent the formation of both ITM and LTM. Conclusions: The injection of either U0126 or GF109203X, which inhibit MAPK and PKC activity respectively, 1 hour prior to training results in the inhibition of both ITM and LTM formation. We further found that NMDA receptor activity was necessary in order for both ITM and LTM formation. http://www.molecularbrain.com/content/3/1/24 David Rosenegger Ken Lukowiak Molecular Brain 2010, 3:24 2010-08-31T00:00:00Z doi:10.1186/1756-6606-3-24 Molecular Brain 1756-6606 3 24 2010-08-31T00:00:00Z PDF K+ channel interacting protein 1 (KChIP1) is a neuronal calcium sensor (NCS) protein that interacts with multiple intracellular molecules. Its physiological function, however, remains largely unknown. We report that KChIP1 is predominantly expressed at GABAergic synapses of a subset of parvalbumin-positive neurons in the brain. Forced expression of KChIP1 in cultured hippocampal neurons increased the frequency of miniature inhibitory postsynaptic currents (mIPSCs), reduced paired pulse facilitation of autaptic IPSCs, and decreases potassium current density. Furthermore, genetic ablation of KChIP1 potentiated potassium current density in neurons and caused a robust enhancement of anxiety-like behavior in mice. Our study suggests that KChIP1 is a synaptic protein that regulates behavioral anxiety by modulating inhibitory synaptic transmission, and drugs that act on KChIP1 may help to treat patients with mood disorders including anxiety. http://www.molecularbrain.com/content/3/1/23 Kun Xia Hui Xiong Yeonsook Shin Danling Wang Tom Deerinck Hiroto Takahashi Mark Ellisman Stuart Lipton Gang Tong Giannina Descalzi Dongxian Zhang Min Zhuo Zhuohua Zhang Molecular Brain 2010, 3:23 2010-08-02T00:00:00Z doi:10.1186/1756-6606-3-23 Molecular Brain 1756-6606 3 23 2010-08-02T00:00:00Z XML Growth factor-induced receptor dimerization and cross-phosphorylation are hallmarks of signal transduction via receptor tyrosine kinases (RTKs). G protein-coupled receptors (GPCRs) can activate RTKs through a process known as transactivation. The prototypical model of RTK transactivation involves ligand-mediated RTK dimerization and cross-phosphorylation. Here, we show that the platelet-derived growth factor receptor β (PDGFRβ) transactivation by the dopamine receptor D4 (DRD4) is not dependent on ligands for PDGFRβ. Furthermore, when PDGFRβ dimerization is inhibited and receptor phosphorylation is suppressed to near basal levels, the receptor maintains its ability to be transactivated and is still effective in signaling to ERK1/2. Hence, the DRD4-PDGFRβ-ERK1/2 pathway can occur independently of a PDGF-like ligand, PDGFRβ cross-phosphorylation and dimerization, which is distinct from other known forms of transactivation of RTKs by GPCRs. http://www.molecularbrain.com/content/3/1/22 Sum Shing Chi Sandra Vetiska Robin Gill Marilyn Hsiung Fang Liu Hubert Van Tol Molecular Brain 2010, 3:22 2010-07-26T00:00:00Z doi:10.1186/1756-6606-3-22 Molecular Brain 1756-6606 3 22 2010-07-26T00:00:00Z XML Synaptic transmission and long-term potentiation (LTP) in the CA1 region of hippocampal slices have been studied during ageing of a double transgenic mouse strain relevant to early-onset familial Alzheimer's disease (AD). This strain, which over-expresses both the 695 amino acid isoform of human amyloid precursor protein (APP) with K670N and M671L mutations and presenilin 1 with the A246E mutation, has accelerated amyloidosis and plaque formation. There was a decrease in synaptic transmission in both wildtype and transgenic mice between 2 and 9 months of age. However, preparing slices from 14 month old animals in kynurenic acid (1 mM) counteracted this age-related deficit. Basal transmission and paired-pulse facilitation was similar between the two groups at all ages (2, 6, 9 and 14 months) tested. Similarly, at all ages LTP, induced either by theta burst stimulation or by multiple tetani, was normal. These data show that a prolonged, substantially elevated level of Aβ are not sufficient to cause deficits in the induction or expression of LTP in the CA1 hippocampal region. http://www.molecularbrain.com/content/3/1/21 Stephen Fitzjohn Frederick Kuenzi Robin Morton Tomas Rosahl Huw Lewis David Smith Guy Seabrook Graham Collingridge Molecular Brain 2010, 3:21 2010-07-14T00:00:00Z doi:10.1186/1756-6606-3-21 Molecular Brain 1756-6606 3 21 2010-07-14T00:00:00Z XML Background: Interactions between dopamine and glutamate in the prefrontal cortex are essential for cognitive functions such as working memory. Modulation of N-methyl-D-aspartic acid (NMDA) receptor functions by dopamine D1 receptor is believed to play a critical role in these functions. The aim of the work reported here is to explore the signaling pathway underlying D1 receptor-mediated trafficking of NMDA receptors in cultured rat prefrontal cortical neurons. Results: Activation of D1 receptor by selective agonist SKF-81297 significantly increased the expression of NR2B subunits. This effect was completely blocked by small interfering RNA knockdown of Fyn, but not Src. Under control conditions, neither Fyn nor Src knockdown exhibited significant effect on basal NR2B expression. D1 stimulation significantly enhanced NR2B insertion into plasma membrane in cultured PFC neurons, a process obstructed by Fyn, but not Src, knockdown. Conclusions: Dopamine D1 receptor-mediated increase of NMDA receptors is thus Fyn kinase dependent. Targeting this signaling pathway may be useful in treating drug addiction and schizophrenia. http://www.molecularbrain.com/content/3/1/20 Jian-Li Hu Gang Liu Yan-Chun Li Wen-Jun Gao Yue-Qiao Huang Molecular Brain 2010, 3:20 2010-06-22T00:00:00Z doi:10.1186/1756-6606-3-20 Molecular Brain 1756-6606 3 20 2010-06-22T00:00:00Z XML Background: The establishment of tissue architecture in the nervous system requires the proper migration and positioning of newly born neurons during embryonic development. Defects in nuclear translocation, a key process in neuronal positioning, are associated with brain diseases such as lissencephaly in humans. Accumulated evidence suggests that the molecular mechanisms controlling neuronal movement are conserved throughout evolution. While the initial events of neuronal migration have been extensively studied, less is known about the molecular details underlying the establishment of neuronal architecture after initial migration. Results: In a search for novel players in the control of photoreceptor (R cell) positioning in the developing fly visual system, we found that misexpression of the RabGAP RN-Tre disrupted the apical localization of R-cell nuclei. RN-Tre interacts with Rab5 and Rab11 in the fly eye. Genetic analysis shows that Rab5, Shi and Rab11 are required for maintaining apical localization of R-cell nuclei. Conclusions: We propose that Rab5, Shi and Rab11 function together in a vesicular transport pathway for regulating R-cell positioning in the developing eye. http://www.molecularbrain.com/content/3/1/19 Tarek Houalla Lei Shi Donald van Meyel Yong Rao Molecular Brain 2010, 3:19 2010-06-11T00:00:00Z doi:10.1186/1756-6606-3-19 Molecular Brain 1756-6606 3 19 2010-06-11T00:00:00Z XML Background: During cerebellar development, Purkinje cells (PCs) form the most elaborate dendritic trees among neurons in the brain, but the mechanism regulating PC arborization remains largely unknown. Geranylgeranyltransferase I (GGT) is a prenyltransferase that is responsible for lipid modification of several signaling proteins, such as Rho family small GTPase Rac1, which has been shown to be involved in neuronal morphogenesis. Here we show that GGT plays an important role in dendritic development of PCs. Results: We found that GGT was abundantly expressed in the developing rat cerebellum, in particular molecular layer (ML), the region enriched with PC dendrites. Inhibition or down-regulation of GGT using small interference RNA (siRNA) inhibited dendritic development of PCs. In contrast, up-regulation of GGT promoted dendritic arborization of PCs. Furthermore, neuronal depolarization induced by high K+ or treatment with brain-derived neurotrophic factor (BDNF) promoted membrane association of Rac1 and dendritic development of PCs in cultured cerebellar slices. The effect of BDNF or high K+ was inhibited by inhibition or down-regulation of GGT. Conclusion: Our results indicate that GGT plays an important role in Purkinje cell development, and suggest a novel role of GGT in neuronal morphogenesis in vivo. http://www.molecularbrain.com/content/3/1/18 Kong-Yan Wu Xiu-Ping Zhou Zhen-Ge Luo Molecular Brain 2010, 3:18 2010-06-11T00:00:00Z doi:10.1186/1756-6606-3-18 Molecular Brain 1756-6606 3 18 2010-06-11T00:00:00Z XML Background: Huntingtin (htt) is a multi-domain protein of 350 kDa that is mutated in Huntington's disease (HD) but whose function is yet to be fully understood. This absence of information is due in part to the difficulty of manipulating large DNA fragments by using conventional molecular cloning techniques. Consequently, few studies have addressed the cellular function(s) of full-length htt and its dysfunction(s) associated with the disease. Results: We describe a flexible synthetic vector encoding full-length htt called pARIS-htt (Adaptable, RNAi Insensitive & Synthetic). It includes synthetic cDNA coding for full-length human htt modified so that: 1) it is improved for codon usage, 2) it is insensitive to four different siRNAs allowing gene replacement studies, 3) it contains unique restriction sites (URSs) dispersed throughout the entire sequence without modifying the translated amino acid sequence, 4) it contains multiple cloning sites at the N and C-ter ends and 5) it is Gateway compatible. These modifications facilitate mutagenesis, tagging and cloning into diverse expression plasmids. Htt regulates dynein/dynactin-dependent trafficking of vesicles, such as brain-derived neurotrophic factor (BDNF)-containing vesicles, and of organelles, including reforming and maintenance of the Golgi near the cell centre. We used tests of these trafficking functions to validate various pARIS-htt constructs. We demonstrated, after silencing of endogenous htt, that full-length htt expressed from pARIS-htt rescues Golgi apparatus reformation following reversible microtubule disruption. A mutant form of htt that contains a 100Q expansion and a htt form devoid of either HAP1 or dynein interaction domains are both unable to rescue loss of endogenous htt. These mutants have also an impaired capacity to promote BDNF vesicular trafficking in neuronal cells. Conclusion: We report the validation of a synthetic gene encoding full-length htt protein that will facilitate analyses of its structure/function. This may help provide relevant information about the cellular dysfunctions operating during the disease. As proof of principle, we show that either polyQ expansion or deletion of key interacting domains within full-length htt protein impairs its function in transport indicating that HD mutation induces defects on intrinsic properties of the protein and further demonstrating the importance of studying htt in its full-length context. http://www.molecularbrain.com/content/3/1/17 Raul Pardo Maria Molina-Calavita Ghislaine Poizat Guy Keryer Sandrine Humbert Frederic Saudou Molecular Brain 2010, 3:17 2010-06-01T00:00:00Z doi:10.1186/1756-6606-3-17 Molecular Brain 1756-6606 3 17 2010-06-01T00:00:00Z XML