Now showing items 41-60 of 77

    • Synaptic Defects in the Spinal and Neuromuscular Circuitry in a Mouse Model of Spinal Muscular Atrophy

      Ling, Karen K. Y.; Lin, Ming-Yi; Zingg, Brian; Feng, Zhihua; Ko, Chien-Ping; Mei, Lin; Department of Neurology; College of Graduate Studies (2010-11-11)
      Spinal muscular atrophy (SMA) is a major genetic cause of death in childhood characterized by marked muscle weakness. To investigate mechanisms underlying motor impairment in SMA, we examined the spinal and neuromuscular circuitry governing hindlimb ambulatory behavior in SMA model mice (SMNÎ 7). In the neuromuscular circuitry, we found that nearly all neuromuscular junctions (NMJs) in hindlimb muscles of SMNÎ 7 mice remained fully innervated at the disease end stage and were capable of eliciting muscle contraction, despite a modest reduction in quantal content. In the spinal circuitry, we observed a â ¼28% loss of synapses onto spinal motoneurons in the lateral column of lumbar segments 3â 5, and a significant reduction in proprioceptive sensory neurons, which may contribute to the 50% reduction in vesicular glutamate transporter 1(VGLUT1)-positive synapses onto SMNÎ 7 motoneurons. In addition, there was an increase in the association of activated microglia with SMNÎ 7 motoneurons. Together, our results present a novel concept that synaptic defects occur at multiple levels of the spinal and neuromuscular circuitry in SMNÎ 7 mice, and that proprioceptive spinal synapses could be a potential target for SMA therapy.
    • The Role of Growth Retardation in Lasting Effects of Neonatal Dexamethasone Treatment on Hippocampal Synaptic Function

      Wang, Yu-Chen; Huang, Chiung-Chun; Hsu, Kuei-Sen; Mei, Lin; Department of Neurology; College of Graduate Studies (2010-09-21)
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    • Diabetes Mellitus, Acute Hyperglycemia, and Ischemic Stroke

      Bruno, Askiel; Liebeskind, David; Hao, Qing; Raychev, Radoslav; Department of Neurology (2010-08-21)
      Opinion statement
    • Differential Regulation of the Variations Induced by Environmental Richness in Adult Neurogenesis as a Function of Time: A Dual Birthdating Analysis

      Llorens-Martí­n, Marí­a; Tejeda, Gonzalo S.; Trejo, José L.; Tsien, Joe Z.; Department of Neurology (2010-08-16)
      Adult hippocampal neurogenesis (AHN) augments after environmental enrichment (EE) and it has been related to some of the anxiolytic, antidepressant and neuroprotective effects of EE. Indeed, it has been suggested that EE specifically modulates hippocampal neurogenic cell populations over the course of time. Here we have used dual-birthdating to study two subpopulations of newborn neuron in mice (Mus musculus): those born at the beginning and at the end of enrichment. In this way, we demonstrate that while short-term cell survival is upregulated after an initial 1 week period of enrichment in 2 month old female mice, after long-term enrichment (2 months) neither cell proliferation nor the survival of the younger newly born cell populations are distinguishable from that observed in non-enriched control mice. In addition, we show that the survival of older newborn neurons alone (i.e. those born at the beginning of the enrichment) is higher than in controls, due to the significantly lower levels of cell death. Indeed, these parameters are rapidly adjusted to the sudden cessation of the EE conditions. These findings suggest both an early selective, long-lasting effect of EE on the neurons born in the initial stages of enrichment, and a quick response when the environment again becomes impoverished. Therefore, EE induces differential effects on distinct subpopulations of newborn neurons depending on the age of the immature cells and on the duration of the EE itself. The interaction of these two parameters constitutes a new, specific regulation of these neurogenic populations that might account for the long-term enrichment's behavioral effects.
    • Synaptic Plasticity and NO-cGMP-PKG Signaling Regulate Pre- and Postsynaptic Alterations at Rat Lateral Amygdala Synapses Following Fear Conditioning

      Ota, Kristie T.; Monsey, Melissa S.; Wu, Melissa S.; Schafe, Glenn E.; Tsien, Joe Z.; Department of Neurology; College of Graduate Studies (2010-06-21)
      In vertebrate models of synaptic plasticity, signaling via the putative â retrograde messengerâ nitric oxide (NO) has been hypothesized to serve as a critical link between functional and structural alterations at pre- and postsynaptic sites. In the present study, we show that auditory Pavlovian fear conditioning is associated with significant and long-lasting increases in the expression of the postsynaptically-localized protein GluR1 and the presynaptically-localized proteins synaptophysin and synapsin in the lateral amygdala (LA) within 24 hrs following training. Further, we show that rats given intra-LA infusion of either the NR2B-selective antagonist Ifenprodil, the NOS inhibitor 7-Ni, or the PKG inhibitor Rp-8-Br-PET-cGMPS exhibit significant decreases in training-induced expression of GluR1, synaptophysin, and synapsin immunoreactivity in the LA, while those rats infused with the PKG activator 8-Br-cGMP exhibit a significant increase in these proteins in the LA. In contrast, rats given intra-LA infusion of the NO scavenger c-PTIO exhibit a significant decrease in synapsin and synaptophysin expression in the LA, but no significant impairment in the expression of GluR1. Finally, we show that intra-LA infusions of the ROCK inhibitor Y-27632 or the CaMKII inhibitor KN-93 impair training-induced expression of GluR1, synapsin, and synaptophysin in the LA. These findings suggest that the NO-cGMP-PKG, Rho/ROCK, and CaMKII signaling pathways regulate fear memory consolidation, in part, by promoting both pre- and post-synaptic alterations at LA synapses. They further suggest that synaptic plasticity in the LA during auditory fear conditioning promotes alterations at presynaptic sites via NO-driven â retrograde signalingâ .
    • Neurexin in Embryonic Drosophila Neuromuscular Junctions

      Chen, Kaiyun; Gracheva, Elena O.; Yu, Szi-Chieh; Sheng, Qi; Richmond, Janet; Featherstone, David E.; Mei, Lin; Department of Neurology; College of Graduate Studies (2010-06-14)
      Background: Neurexin is a synaptic cell adhesion protein critical for synapse formation and function. Mutations in neurexin and neurexin-interacting proteins have been implicated in several neurological diseases. Previous studies have described Drosophila neurexin mutant phenotypes in third instar larvae and adults. However, the expression and function of Drosophila neurexin early in synapse development, when neurexin function is thought to be most important, has not been described.
    • Molecular Composition of Staufen2-Containing Ribonucleoproteins in Embryonic Rat Brain

      Maher-Laporte, Marjolaine; Berthiaume, Frederic; Moreau, Mireille; Julien, Louis-Andre; Lapointe, Gabriel; Mourez, Michael; DesGroseillers, Luc; Mei, Lin; Department of Neurology; College of Graduate Studies (2010-06-28)
      Messenger ribonucleoprotein particles (mRNPs) are used to transport mRNAs along neuronal dendrites to their site of translation. Numerous mRNA-binding and regulatory proteins within mRNPs finely regulate the fate of bound-mRNAs. Their specific combination defines different types of mRNPs that in turn are related to specific synaptic functions. One of these mRNA-binding proteins, Staufen2 (Stau2), was shown to transport dendritic mRNAs along microtubules. Its knockdown expression in neurons was shown to change spine morphology and synaptic functions. To further understand the molecular mechanisms by which Stau2 modulates synaptic function in neurons, it is important to identify and characterize protein co-factors that regulate the fate of Stau2-containing mRNPs. To this end, a proteomic approach was used to identify co-immunoprecipitated proteins in Staufen2-containing mRNPs isolated from embryonic rat brains. The proteomic approach identified mRNA-binding proteins (PABPC1, hnRNP H1, YB1 and hsc70), proteins of the cytoskeleton (a- and b-tubulin) and RUFY3 a poorly characterized protein. While PABPC1 and YB1 associate with Stau2-containing mRNPs through RNAs, hsc70 is directly bound to Stau2 and this interaction is regulated by ATP. PABPC1 and YB1 proteins formed puncta in dendrites of embryonic rat hippocampal neurons. However, they poorly co-localized with Stau2 in the large dendritic complexes suggesting that they are rather components of Stau2-containing mRNA particles. All together, these results represent a further step in the characterization of Stau2-containing mRNPs in neurons and provide new tools to study and understand how Stau2-containing mRNPs are transported, translationally silenced during transport and/or locally expressed according to cell needs.
    • beta-Catenin Regulates Intercellular Signalling Networks and Cell-Type Specific Transcription in the Developing Mouse Midbrain-Rhombomere 1 Region

      Chilov, Dmitri; Sinjushina, Natalia; Saarimaki-Vire, Jonna; Taketo, Makoto M.; Partanen, Juha; Mei, Lin; Department of Neurology (2010-06-3)
      b-catenin is a multifunctional protein involved in both signalling by secreted factors of Wnt family and regulation of the cellular architecture. We show that b-catenin stabilization in mouse midbrain-rhombomere1 region leads to robust upregulation of several Wnt signalling target genes, including Fgf8. Suggestive of direct transcriptional regulation of the Fgf8 gene, b-catenin stabilization resulted in Fgf8 up-regulation also in other tissues, specifically in the ventral limb ectoderm. Interestingly, stabilization of b-catenin rapidly caused down-regulation of the expression of Wnt1 itself, suggesting a negative feedback loop. The changes in signal molecule expression were concomitant with deregulation of anteriorposterior and dorso-ventral patterning. The transcriptional regulatory functions of b-catenin were confirmed by b-catenin loss-of-function experiments. Temporally controlled inactivation of b-catenin revealed a cell-autonomous role for b-catenin in the maintenance of cell-type specific gene expression in the progenitors of midbrain dopaminergic neurons. These results highlight the role of b-catenin in establishment of neuroectodermal signalling centers, promoting region-specific gene expression and regulation of cell fate determination.
    • Behavioral Consequences of NMDA Antagonist-Induced Neuroapoptosis in the Infant Mouse Brain

      Yuede, Carla M.; Wozniak, David F.; Creeley, Catherine E.; Taylor, George T.; Olney, John W.; Farber, Nuri B.; Mei, Lin; Department of Neurology (2010-06-29)
      Background: Exposure to NMDA glutamate antagonists during the brain growth spurt period causes widespread neuroapoptosis in the rodent brain. This period in rodents occurs during the first two weeks after birth, and corresponds to the third trimester of pregnancy and several years after birth in humans. The developing human brain may be exposed to NMDA antagonists through drug-abusing mothers or through anesthesia.
    • The Transcription Factor Cux1 Regulates Dendritic Morphology of Cortical Pyramidal Neurons

      Li, Ning; Zhao, Chun-Tao; Wang, Ying; Yuan, Xiao-Bing; Mei, Lin; Department of Neurology; College of Graduate Studies (2010-05-11)
      In the murine cerebral cortex, mammalian homologues of the Cux family transcription factors, Cux1 and Cux2, have been identified as restricted molecular markers for the upper layer (II-IV) pyramidal neurons. However, their functions in cortical development are largely unknown. Here we report that increasing the intracellular level of Cux1, but not Cux2, reduced the dendritic complexity of cultured cortical pyramidal neurons. Consistently, reducing the expression of Cux1 promoted the dendritic arborization in these pyramidal neurons. This effect required the existence of the DNA-binding domains, hence the transcriptional passive repression activity of Cux1. Analysis of downstream signals suggested that Cux1 regulates dendrite development primarily through suppressing the expression of the cyclin-dependent kinase inhibitor p27Kip1, and RhoA may mediate the regulation of dendritic complexity by Cux1 and p27. Thus, Cux1 functions as a negative regulator of dendritic complexity for cortical pyramidal neurons.
    • Natural Spike Trains Trigger Short- and Long-Lasting Dynamics at Hippocampal Mossy Fiber Synapses in Rodents

      Gundlfinger, Anja; Breustedt, Jorg; Sullivan, David; Schmitz, Dietmar; Tsien, Joe Z.; Department of Neurology; College of Graduate Studies (2010-04-1)
      Background: Synapses exhibit strikingly different forms of plasticity over a wide range of time scales, from milliseconds to hours. Studies on synaptic plasticity typically use constant-frequency stimulation to activate synapses, whereas in vivo activity of neurons is irregular.
    • Homer1a-Dependent Crosstalk Between NMDA and Metabotropic Glutamate Receptors in Mouse Neurons

      Bertaso, Federica; Roussignol, Gautier; Worley, Paul; Bockaert, Joël; Fagni, Laurent; Ango, Fabrice; Mei, Lin; Department of Neurology; College of Graduate Studies (2010-03-18)
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    • TGF-β Inhibition Restores Terminal Osteoblast Differentiation to Suppress Myeloma Growth

      Takeuchi, Kyoko; Abe, Masahiro; Hiasa, Masahiro; Oda, Asuka; Amou, Hiroe; Kido, Shinsuke; Harada, Takeshi; Tanaka, Osamu; Miki, Hirokazu; Nakamura, Shingen; et al. (2010-03-25)
      Background: Multiple myeloma (MM) expands almost exclusively in the bone marrow and generates devastating bone lesions, in which bone formation is impaired and osteoclastic bone resorption is enhanced. TGF-β, a potent inhibitor of terminal osteoblast (OB) differentiation, is abundantly deposited in the bone matrix, and released and activated by the enhanced bone resorption in MM. The present study was therefore undertaken to clarify the role of TGF-β and its inhibition in bone formation and tumor growth in MM.
    • Mutations in AKAP5 Disrupt Dendritic Signaling Complexes and Lead to Electrophysiological and Behavioral Phenotypes in Mice

      Weisenhaus, Michael; Allen, Margaret L.; Yang, Linghai; Lu, Yuan; Nichols, C. Blake; Su, Thomas; Hell, Johannes W.; McKnight, G. Stanley; Mei, Lin; Department of Neurology; et al. (2010-04-23)
      AKAP5 (also referred to as AKAP150 in rodents and AKAP79 in humans) is a scaffolding protein that is highly expressed in neurons and targets a variety of signaling molecules to dendritic membranes. AKAP5 interacts with PKA holoenzymes containing RIIa or RIIb as well as calcineurin (PP2B), PKC, calmodulin, adenylyl cyclase type V/VI, L-type calcium channels, and b-adrenergic receptors. AKAP5 has also been shown to interact with members of the MAGUK family of PSD-scaffolding proteins including PSD95 and SAP97 and target signaling molecules to receptors and ion channels in the postsynaptic density (PSD). We created two lines of AKAP5 mutant mice: a knockout of AKAP5 (KO) and a mutant that lacks the PKA binding domain of AKAP5 (D36). We find that PKA is delocalized in both the hippocampus and striatum of KO and D36 mice indicating that other neural AKAPs cannot compensate for the loss of PKA binding to AKAP5. In AKAP5 mutant mice, a significant fraction of PKA becomes localized to dendritic shafts and this correlates with increased binding to microtubule associated protein-2 (MAP2). Electrophysiological and behavioral analysis demonstrated more severe deficits in both synaptic plasticity and operant learning in the D36 mice compared with the complete KO animals. Our results indicate that the targeting of calcineurin or other binding partners of AKAP5 in the absence of the balancing kinase, PKA, leads to a disruption of synaptic plasticity and results in learning and memory defects.
    • Dystroglycan and Mitochondrial Ribosomal Protein L34 Regulate Differentiation in the Drosophila Eye

      Zhan, Yougen; Melian, Nadia Y.; Pantoja, Mario; Haines, Nicola; Ruohola-Baker, Hannele; Bourque, Charles W.; Rao, Yong; Carbonetto, Salvatore; Mei, Lin; Department of Neurology (2010-05-5)
      Mutations that diminish the function of the extracellular matrix receptor Dystroglycan (DG) result in muscular dystrophies, with associated neuronal migration defects in the brain and mental retardation e.g. Muscle Eye Brain Disease. To gain insight into the function of DG in the nervous system we initiated a study to examine its contribution to development of the eye of Drosophila melanogaster. Immuno-histochemistry showed that DG is concentrated on the apical surface of photoreceptors (R) cells during specification of cell-fate in the third instar larva and is maintained at this location through early pupal stages. In point mutations that are null for DG we see abortive R cell elongation during differentiation that first appears in the pupa and results in stunted R cells in the adult. Overexpression of DG in R cells results in a small but significant increase in their size. R cell differentiation defects appear at the same stage in a deficiency line Df(2R)Dg248 that affects Dg and the neighboring mitochondrial ribosomal gene, mRpL34. In the adult, these flies have severely disrupted R cells as well as defects in the lens and ommatidia. Expression of an mRpL34 transgene rescues much of this phenotype. We conclude that DG does not affect neuronal commitment but functions R cell autonomously to regulate neuronal elongation during differentiation in the pupa. We discuss these findings in view of recent work implicating DG as a regulator of cell metabolism and its genetic interaction with mRpL34, a member of a class of mitochondrial genes essential for normal metabolic function.
    • Analysis of the Potential Role of GluA4 Carboxyl-Terminus in PDZ Interactions

      Coleman, Sarah K.; Cai, Chunlin; Kalkkinen, Nisse; Korpi, Esa R.; Keinanen, Kari; Mei, Lin; Department of Neurology; College of Graduate Studies (2010-01-14)
      Background: Specific delivery to synapses of a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors with long-tailed subunits is believed to be a key event in many forms of activity-dependent changes in synaptic strength. GluA1, the best characterized long-tailed AMPA receptor subunit, contains a C-terminal class I PDZ binding motif, which mediates its interaction with scaffold and trafficking proteins, including synapse-associated protein 97 (SAP97). In GluA4, another long-tailed subunit implicated in synaptic plasticity, the PDZ motif is blocked by a single proline residue. This feature is highly conserved in vertebrates, whereas the closest invertebrate homologs of GluA4 have a canonical class I PDZ binding motif. In this work, we have examined the role of GluA4 in PDZ interactions
    • Vertebrate Lrig3-ErbB Interactions Occur In Vitro but Are Unlikely to Play a Role in Lrig3-Dependent Inner Ear Morphogenesis

      Abraira, Victoria E.; Satoh, Takunori; Fekete, Donna M.; Goodrich, Lisa V.; Mei, Lin; Department of Neurology; College of Graduate Studies (2010-02-1)
      Background: The Lrig genes encode a family of transmembrane proteins that have been implicated in tumorigenesis, psoriasis, neural crest development, and complex tissue morphogenesis. Whether these diverse phenotypes reflect a single underlying cellular mechanism is not known. However, Lrig proteins contain evolutionarily conserved ectodomains harboring both leucine-rich repeats and immunoglobulin domains, suggesting an ability to bind to common partners. Previous studies revealed that Lrig1 binds to and inhibits members of the ErbB family of receptor tyrosine kinases by inducing receptor internalization and degradation. In addition, other receptor tyrosine kinase binding partners have been identified for both Lrig1 and Lrig3, leaving open the question of whether defective ErbB signaling is responsible for the observed mouse phenotypes.
    • The Function of Cortactin in the Clustering of Acetylcholine Receptors at the Vertebrate Neuromuscular Junction

      Madhavan, Raghavan; Gong, Zhuolin L.; Ma, Jin Jin; Chan, Ariel W. S.; Peng, H. Benjamin; Mei, Lin; Department of Neurology (2009-12-29)
      Background: Postsynaptic enrichment of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction (NMJ) depends on the activation of the muscle receptor tyrosine MuSK by neural agrin. Agrin-stimulation of MuSK is known to initiate an intracellular signaling cascade that leads to the clustering of AChRs in an actin polymerization-dependent manner, but the molecular steps which link MuSK activation to AChR aggregation remain incompletely defined.
    • Regulation of Adipose Tissue Stromal Cells Behaviors by Endogenic Oct4 Expression Control

      Kim, Jung Hwan; Jee, Min Ki; Lee, So Young; Han, Tae Hee; Kim, Bong Sun; Kang, Kyung Sun; Kang, Soo Kyung; Mei, Lin; Department of Neurology; College of Graduate Studies (2009-09-24)
      Background: To clarify the role of the POU domain transcription factor Oct4 in Adipose Tissue Stromal Cells (ATSCs), we investigated the regulation of Oct4 expression and other embryonic genes in fully differentiated cells, in addition to identifying expression at the gene and protein levels. The ATSCs and several immature cells were routinely expressing Oct4 protein before and after differentiating into specific lineages.
    • Adult Type 3 Adenylyl Cyclaseâ Deficient Mice Are Obese

      Wang, Zhenshan; Li, Vicky; Chan, Guy C. K.; Phan, Trongha; Nudelman, Aaron S.; Xia, Zhengui; Storm, Daniel R.; Tsien, Joe Z.; Department of Neurology; College of Graduate Studies (2009-09-11)
      Background: A recent study of obesity in Swedish men found that polymorphisms in the type 3 adenylyl cyclase (AC3) are associated with obesity, suggesting the interesting possibility that AC3 may play a role in weight control. Therefore, we examined the weight of AC3 mice over an extended period of time.