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Role of transverse bands in maintaining paranodal structure and axolemmal domain organization in myelinated nerve fibers: Effect on longevity in dysmyelinated mutant mice
Mierzwa, Amanda J; Arevalo, Juan-Carlos; Schiff, Rolf; Chao, Moses V; Rosenbluth, Jack
The consequences of dysmyelination are poorly understood and vary widely in severity. The shaking mouse, a quaking allele, is characterized by severe central nervous system (CNS) dysmyelination and demyelination, a conspicuous action tremor, and seizures in approximately 25% of animals, but with normal muscle strength and a normal lifespan. In this study we compare this mutant with other dysmyelinated mutants including the ceramide sulfotransferase deficient (CST-/-) mouse, which are more severely affected behaviorally, to determine what might underlie the differences between them with respect to behavior and longevity. Examination of the paranodal junctional region of CNS myelinated fibers shows that 'transverse bands,' a component of the junction, are present in nearly all shaking paranodes but in only a minority of CST-/- paranodes. The number of terminal loops that have transverse bands within a paranode and the number of transverse bands per unit length are only moderately reduced in the shaking mutant, compared with controls, but markedly reduced in CST-/- mice. Immunofluorescence studies also show that although the nodes of the shaking mutant are somewhat longer than normal, Na(+) and K(+) channels remain separated, distinguishing this mutant from CST-/- mice and others that lack transverse bands. We conclude that the essential difference between the shaking mutant and others more severely affected is the presence of transverse bands, which serve to stabilize paranodal structure over time as well as the organization of the axolemmal domains, and that differences in the prevalence of transverse bands underlie the marked differences in progressive neurological impairment and longevity among dysmyelinated mouse mutants. J. Comp. Neurol. 518:2841-2853, 2010. (c) 2010 Wiley-Liss, Inc
PMCID:2879089
PMID: 20506478
ISSN: 1096-9861
CID: 109814
The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus
Ninan, Ipe; Bath, Kevin G; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R; Lee, Francis S; Chao, Moses V
The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus
PMCID:2911131
PMID: 20592208
ISSN: 1529-2401
CID: 110671
Activation of Adenosine A2A Receptors Induces TrkB Translocation and Increases BDNF-Mediated Phospho-TrkB Localization in Lipid Rafts: Implications for Neuromodulation
Assaife-Lopes, Natalia; Sousa, Vasco C; Pereira, Daniela B; Ribeiro, Joaquim A; Chao, Moses V; Sebastiao, Ana M
Brain-derived neurotrophic factor (BDNF) signaling is critical for neuronal development and transmission. Recruitment of TrkB receptors to lipid rafts has been shown to be necessary for the activation of specific signaling pathways and modulation of neurotransmitter release by BDNF. Since TrkB receptors are known to be modulated by adenosine A(2A) receptor activation, we hypothesized that activation of A(2A) receptors could influence TrkB receptor localization among different membrane microdomains. We found that adenosine A(2A) receptor agonists increased the levels of TrkB receptors in the lipid raft fraction of cortical membranes and potentiated BDNF-induced augmentation of phosphorylated TrkB levels in lipid rafts. Blockade of the clathrin-mediated endocytosis with monodansylcadaverine (100 mum) did not modify the effects of the A(2A) receptor agonists but significantly impaired BDNF effects on TrkB recruitment to lipid rafts. The effect of A(2A) receptor activation in TrkB localization was mimicked by 5 mum forskolin, an adenylyl cyclase activator. Also, it was blocked by the PKA inhibitors Rp-cAMPs and PKI-(14-22), and by the Src-family kinase inhibitor PP2. Moreover, removal of endogenous adenosine or disruption of lipid rafts reduced BDNF stimulatory effects on glutamate release from cortical synaptosomes. Lipid raft integrity was also required for the effects of BDNF on hippocampal long-term potentiation at CA1 synapses. Our data demonstrate, for the first time, a BDNF-independent recruitment of TrkB receptors to lipid rafts induced by activation of adenosine A(2A) receptors, with functional consequences for TrkB phosphorylation and BDNF-induced modulation of neurotransmitter release and hippocampal plasticity
PMID: 20573894
ISSN: 1529-2401
CID: 110091
Localization of BDNF mRNA with the Huntington's disease protein in rat brain
Ma, Bin; Culver, Brady P; Baj, Gabriele; Tongiorgi, Enrico; Chao, Moses V; Tanese, Naoko
ABSTRACT: BACKGROUND: Studies have implicated reduced levels of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Huntington's disease. Mutant huntingtin (Htt) protein was previously reported to decrease BDNF gene transcription and axonal transport of BDNF. We recently showed that wild-type Htt is associated with the Argonaute 2 microRNA-processing enzyme involved in gene silencing. In dendrites, Htt co-localizes with components of neuronal granules and mRNAs, indicating that it might play a role in post-transcriptional processing/transport of dendritic mRNAs. RESULTS: We conducted imaging experiments in cultured cortical neurons to demonstrate the co-localization of endogenous Htt and BDNF mRNA in fixed cells, and co-trafficking of BDNF 3'UTR mRNA with endogenous and fluorescently tagged Htt in live neurons. We used an enhanced technique that combines FISH and immunofluorescent staining to co-localize BDNF mRNA with Htt, Ago2, CPEB and dynein in thick vibratome sections of the rat cortex. CONCLUSIONS: In cultured neurons and sections of the rat cortex, we found BDNF mRNA associated with Htt and components of neuronal RNA granules, which are centers for regulating RNA transport and local translation. Htt may play a role in post-transcriptional transport/targeting of mRNA for BDNF, thus contributing to neurotrophic support and neuron survival
PMCID:2889995
PMID: 20507609
ISSN: 1750-1326
CID: 110078
Organophosphates induce distal axonal damage, but not brain oedema, by inactivating neuropathy target esterase
Read, David J; Li, Yong; Chao, Moses V; Cavanagh, John B; Glynn, Paul
Single doses of organophosphorus compounds (OP) which covalently inhibit neuropathy target esterase (NTE) can induce lower-limb paralysis and distal damage in long nerve axons. Clinical signs of neuropathy are evident 3weeks post-OP dose in humans, cats and chickens. By contrast, clinical neuropathy in mice following acute dosing with OPs or any other toxic compound has never been reported. Moreover, dosing mice with ethyloctylphosphonofluoridate (EOPF) - an extremely potent NTE inhibitor - causes a different (subacute) neurotoxicity with brain oedema. These observations have raised the possibility that mice are intrinsically resistant to neuropathies induced by acute toxic insult, but may incur brain oedema, rather than distal axonal damage, when NTE is inactivated. Here we provide the first report that hind-limb dysfunction and extensive axonal damage can occur in mice 3weeks after acute dosing with a toxic compound, bromophenylacetylurea. Three weeks after acutely dosing mice with neuropathic OPs no clinical signs were observed, but distal lesions were present in the longest spinal sensory axons. Similar lesions were evident in undosed nestin-cre:NTEfl/fl mice in which NTE had been genetically-deleted from neural tissue. The extent of OP-induced axonal damage in mice was related to the duration of NTE inactivation and, as reported in chickens, was promoted by post-dosing with phenylmethanesulfonylfluoride. However, phenyldipentylphosphinate, another promoting compound in chickens, itself induced in mice lesions different from the neuropathic OP type. Finally, EOPF induced subacute neurotoxicity with brain oedema in both wild-type and nestin-cre:NTEfl/fl mice indicating that the molecular target for this effect is not neural NTE
PMID: 20188121
ISSN: 1096-0333
CID: 145799
A role for huntington disease protein in dendritic RNA granules
Savas, Jeffrey N; Ma, Bin; Deinhardt, Katrin; Culver, Brady P; Restituito, Sophie; Wu, Ligang; Belasco, Joel G; Chao, Moses V; Tanese, Naoko
Regulated transport and local translation of mRNA in neurons are critical for modulating synaptic strength, maintaining proper neural circuitry, and establishing long term memory. Neuronal RNA granules are ribonucleoprotein particles that serve to transport mRNA along microtubules and control local protein synthesis in response to synaptic activity. Studies suggest that neuronal RNA granules share similar structures and functions with somatic P-bodies. We recently reported that the Huntington disease protein huntingtin (Htt) associates with Argonaute (Ago) and localizes to cytoplasmic P-bodies, which serve as sites of mRNA storage, degradation, and small RNA-mediated gene silencing. Here we report that wild-type Htt associates with Ago2 and components of neuronal granules and co-traffics with mRNA in dendrites. Htt was found to co-localize with RNA containing the 3'-untranslated region sequence of known dendritically targeted mRNAs. Knockdown of Htt in neurons caused altered localization of mRNA. When tethered to a reporter construct, Htt down-regulated reporter gene expression in a manner dependent on Ago2, suggesting that Htt may function to repress translation of mRNAs during transport in neuronal granules
PMCID:2857123
PMID: 20185826
ISSN: 1083-351x
CID: 109209
Trophic factors: 50 years of growth
Chao, Moses V; Ip, Nancy Y
PMID: 20186706
ISSN: 1932-8451
CID: 108793
Sciatic nerve injury model in the axolotl: functional, electrophysiological, and radiographic outcomes
Kropf, Nina; Krishnan, Kartik; Chao, Moses; Schweitzer, Mark; Rosenberg, Zehava; Russell, Stephen M
OBJECT: The 2 aims of this study were as follows: 1) to establish outcome measures of nerve regeneration in an axolotl model of peripheral nerve injury; and 2) to define the timing and completeness of reinnervation in the axolotl following different types of sciatic nerve injury. METHODS: The sciatic nerves in 36 axolotls were exposed bilaterally in 3 groups containing 12 animals each: Group 1, left side sham, right side crush; Group 2, left side sham, right side nerve resected and proximal stump buried; and Group 3 left side cut and sutured, right side cut and sutured with tibial and peroneal divisions reversed. Outcome measures included the following: 1) an axolotl sciatic functional index (ASFI) derived from video swim analysis; 2) motor latencies; and 3) MR imaging evaluation of nerve and muscle edema. RESULTS: For crush injuries, the ASFI returned to baseline by 2 weeks, as did MR imaging parameters and motor latencies. For buried nerves, the ASFI returned to 20% below baseline by 8 weeks, with motor evoked potentials present. On MR imaging, nerve edema peaked at 3 days postintervention and gradually normalized over 12 weeks, whereas muscle denervation was present until a gradual decrease was seen between 4 and 12 weeks. For cut nerves, the ASFI returned to 20% below baseline by Week 4, where it plateaued. Motor evoked potentials were observed at 2-4 weeks, but with an increased latency until Week 6, and MR imaging analysis revealed muscle denervation for 4 weeks. CONCLUSIONS: Multiple outcome measures in which an axolotl model of peripheral nerve injury is used have been established. Based on historical controls, recovery after nerve injury appears to occur earlier and is more complete than in rodents. Further investigation using this model as a successful 'blueprint' for nerve regeneration in humans is warranted
PMID: 19764825
ISSN: 1933-0693
CID: 120633
Trk activation in the secretory pathway promotes Golgi fragmentation
Schecterson, Leslayann C; Hudson, Mark P; Ko, Mabel; Philippidou, Polyxeni; Akmentin, Wendy; Wiley, Jesse; Rosenblum, Elise; Chao, Moses V; Halegoua, Simon; Bothwell, Mark
Activation of nascent receptor tyrosine kinases within the secretory pathway has been reported, yet the consequences of intracellular activation are largely unexplored. We report that overexpression of the Trk neurotrophin receptors causes accumulation of autoactivated receptors in the ER-Golgi intermediate compartment. Autoactivated receptors exhibit inhibited Golgi-mediated processing and they inhibit Golgi-mediated processing of other co-expressed transmembrane proteins, apparently by inducing fragmentation of the Golgi apparatus. Signaling from G protein-coupled receptors is known to induce Trk transactivation. Transactivation of nascent TrkB in hippocampal neurons resulting from exposure to the neuropeptide PACAP caused Golgi fragmentation, whereas BDNF-dependent activation of TrkB did not. TrkB-mediated Golgi fragmentation employs a MEK-dependent signaling pathway resembling that implicated in regulation of Golgi fragmentation in mitotic cells. Neuronal Golgi fragments, in the form of dendritically localized Golgi outposts, are important determinants of dendritic growth and branching. The capacity of transactivated TrkB to enhance neuronal Golgi fragmentation may represent a novel mechanism regulating neural plasticity
PMID: 20123019
ISSN: 1095-9327
CID: 133480
Nuclear localization of the p75 neurotrophin receptor intracellular domain
Parkhurst, Christopher N; Zampieri, Niccolo; Chao, Moses V
The p75 neurotrophin receptor, a member of the tumor necrosis factor superfamily of receptors, undergoes an alpha-secretase-mediated release of its extracellular domain, followed by a gamma-secretase-mediated intramembrane cleavage. Like amyloid precursor protein and Notch, gamma-secretase cleavage of the p75 receptor releases an intracellular domain (ICD). However, it has been experimentally challenging to determine the precise subcellular localization and functional consequences of the p75 ICD. Here, we utilized a nuclear translocation assay and biochemical fractionation approaches to follow the fate of the ICD. We found that the p75 ICD can translocate to the nucleus to activate a green fluorescent protein reporter gene. Furthermore, the p75 ICD was localized in nuclear fractions. Chromatin immunoprecipitation experiments indicated that nerve growth factor induced the association of endogenous p75 with the cyclin E(1) promoter. Expression of the p75 ICD resulted in modulation of gene expression from this locus. These results suggest that the p75 ICD generated by gamma-secretase cleavage is capable of modulating transcriptional events in the nucleus
PMCID:2820764
PMID: 20022966
ISSN: 0021-9258
CID: 107370