Publications (47)583.53 Total impact
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Article: Retraction Notice to: Enhanced Polyubiquitination of Shank3 and NMDA Receptor in a Mouse Model of Autism.
Cell 01/2013; 152(1-2):367. · 32.40 Impact Factor -
Article: Characterizing the conductance underlying depolarization-induced slow current (DISC) in cerebellar Purkinje cells.
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ABSTRACT: Brief strong depolarization of cerebellar Purkinje cells produces a slow inward cation current (DISC; depolarization-induced slow current). Previous work has shown that DISC is triggered by voltage-sensitive Ca influx in the Purkinje cell and is attenuated by blockers of vesicular loading and fusion. Here, we have sought to characterize the ion channel(s) underlying the DISC conductance. While the brief depolarizing steps that triggered DISC were associated with a large Ca transient, the onset of DISC current corresponded only with the Ca transient decay phase. Furthermore, substitution of external Na with the impermeant cation NMDG produced a complete and reversible block of DISC, suggesting that the DISC conductance was not Ca-permeant. TRPM4 and TRPM5 are nonselective cation channels that are opened by Ca transients but which do not flux Ca. They are expressed in Purkinje cells of the posterior cerebellum, where DISC is large, and, in these cells, DISC is strongly attenuated by nonselective blockers of TRPM4/5. However, measurement of DISC currents in Purkinje cells derived from TRPM4 null, TRPM5 null and double null mice as well as wild-type mice with TRPM4 shRNA knockdown showed a partial attenuation with 35-46% of current remaining. Thus, while the DISC conductance is Ca-triggered, Na permeant and Ca impermeant, suggesting a role for TRPM4 and TRPM5, these ion channels are not absolutely required for DISC.Journal of Neurophysiology 11/2012; · 3.32 Impact Factor -
Article: Astrocyte inositol triphosphate receptor type 2 and cytosolic phospholipase A2 alpha regulate arteriole responses in mouse neocortical brain slices.
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ABSTRACT: Functional hyperemia of the cerebral vascular system matches regional blood flow to the metabolic demands of the brain. One current model of neurovascular control holds that glutamate released by neurons activates group I metabotropic glutamate receptors (mGluRs) on astrocytes, resulting in the production of diffusible messengers that act to regulate smooth muscle cells surrounding cerebral arterioles. The acute mouse brain slice is an experimental system in which changes in arteriole diameter can precisely measured with light microscopy. Stimulation of the brain slice triggers specific cellular responses that can be correlated to changes in arteriole diameter. Here we used inositol trisphosphate receptor type 2 (IP(3)R2) and cytosolic phospholipase A(2) alpha (cPLA(2)α) deficient mice to determine if astrocyte mGluR activation coupled to IP(3)R2-mediated Ca(2+) release and subsequent cPLA(2)α activation is required for arteriole regulation. We measured changes in astrocyte cytosolic free Ca(2+) and arteriole diameters in response to mGluR agonist or electrical field stimulation in acute neocortical mouse brain slices maintained in 95% or 20% O(2). Astrocyte Ca(2+) and arteriole responses to mGluR activation were absent in IP(3)R2(-/-) slices. Astrocyte Ca(2+) responses to mGluR activation were unchanged by deletion of cPLA(2)α but arteriole responses to either mGluR agonist or electrical stimulation were ablated. The valence of changes in arteriole diameter (dilation/constriction) was dependent upon both stimulus and O(2) concentration. Neuron-derived NO and activation of the group I mGluRs are required for responses to electrical stimulation. These findings indicate that an mGluR/IP(3)R2/cPLA(2)α signaling cascade in astrocytes is required to transduce neuronal glutamate release into arteriole responses.PLoS ONE 01/2012; 7(8):e42194. · 4.09 Impact Factor -
Article: A late phase of LTD in cultured cerebellar Purkinje cells requires persistent dynamin-mediated endocytosis.
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ABSTRACT: Long-term synaptic depression (LTD) of cerebellar parallel fiber-Purkinje cell synapses is a form of use-dependent synaptic plasticity that may be studied in cell culture. One form of LTD is induced postsynaptically through an mGlu1/Ca influx/protein kinase Cα (PKCα) cascade, and its initial expression requires phosphorylation of ser-880 in the COOH-terminal PDZ-ligand region of GluA2 and consequent binding of PICK1. This triggers postsynaptic clathrin/dynamin-mediated endocytosis of GluA2-containing surface AMPA receptors. Cerebellar LTD also has a late phase beginning 45-60 min after induction that is blocked by transcription or translation inhibitors. Here, I have sought to determine the expression mechanism of this late phase of LTD by applying various drugs and peptides after the late phase has been established. Neither bath application of mGluR1 antagonists (JNJ-16259685, LY-456236) nor the PKC inhibitor GF-109203X starting 60-70 min after LTD induction attenuated the late phase. Similarly, achieving the whole cell configuration with a second pipette loaded with the peptide PKC inhibitor PKC(19-36) starting 60 min postinduction also failed to alter the late phase. Late internal perfusion with peptides designed to disrupt PICK1-GLUA2 interaction or PICK1 dimerization failed to impact late phase LTD expression. However, late internal perfusion with two different blockers of dynamin, the drug dynasore and a dynamin inhibitory peptide (QVPSRPNRAP), produced rapid and complete reversal of cerebellar LTD expression. These findings suggest that the protein synthesis-dependent late phase of LTD requires persistent dynamin-mediated endocytosis, but not persistent PICK1-GluA2 binding nor persistent activation of the upstream mGluR1/PKCα signaling cascade.Journal of Neurophysiology 11/2011; 107(1):448-54. · 3.32 Impact Factor -
Article: Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism.
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ABSTRACT: We have created a mouse genetic model that mimics a human mutation of Shank3 that deletes the C terminus and is associated with autism. Expressed as a single copy [Shank3(+/ΔC) mice], Shank3ΔC protein interacts with the wild-type (WT) gene product and results in >90% reduction of Shank3 at synapses. This "gain-of-function" phenotype is linked to increased polyubiquitination of WT Shank3 and its redistribution into proteasomes. Similarly, the NR1 subunit of the NMDA receptor is reduced at synapses with increased polyubiquitination. Assays of postsynaptic density proteins, spine morphology, and synapse number are unchanged in Shank3(+/ΔC) mice, but the amplitude of NMDAR responses is reduced together with reduced NMDAR-dependent LTP and LTD. Reciprocally, mGluR-dependent LTD is markedly enhanced. Shank3(+/ΔC) mice show behavioral deficits suggestive of autism and reduced NMDA receptor function. These studies reveal a mechanism distinct from haploinsufficiency by which mutations of Shank3 can evoke an autism-like disorder.Cell 05/2011; 145(5):758-72. · 32.40 Impact Factor -
Article: Reevaluating the role of LTD in cerebellar motor learning.
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ABSTRACT: Long-term depression at parallel fiber-Purkinje cell synapses (PF-PC LTD) has been proposed to be required for cerebellar motor learning. To date, tests of this hypothesis have sought to interfere with receptors (mGluR1) and enzymes (PKC, PKG, or αCamKII) necessary for induction of PF-PC LTD and thereby determine if cerebellar motor learning is impaired. Here, we tested three mutant mice that target the expression of PF-PC LTD by blocking internalization of AMPA receptors. Using three different cerebellar coordination tasks (adaptation of the vestibulo-ocular reflex, eyeblink conditioning, and locomotion learning on the Erasmus Ladder), we show that there is no motor learning impairment in these mutant mice that lack PF-PC LTD. These findings demonstrate that PF-PC LTD is not essential for cerebellar motor learning.Neuron 04/2011; 70(1):43-50. · 14.74 Impact Factor -
Article: Homeostatic scaling requires group I mGluR activation mediated by Homer1a.
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ABSTRACT: Homeostatic scaling is a non-Hebbian form of neural plasticity that maintains neuronal excitability and informational content of synaptic arrays in the face of changes of network activity. Here, we demonstrate that homeostatic scaling is dependent on group I metabotropic glutamate receptor activation that is mediated by the immediate early gene Homer1a. Homer1a is transiently upregulated during increases in network activity and evokes agonist-independent signaling of group I mGluRs that scales down the expression of synaptic AMPA receptors. Homer1a effects are dynamic and play a role in the induction of scaling. Similar to mGluR-LTD, Homer1a-dependent scaling involves a reduction of tyrosine phosphorylation of GluA2 (GluR2), but is distinct in that it exploits a unique signaling property of group I mGluR to confer cell-wide, agonist-independent activation of the receptor. These studies reveal an elegant interplay of mechanisms that underlie Hebbian and non-Hebbian plasticity.Neuron 12/2010; 68(6):1128-42. · 14.74 Impact Factor -
Article: SRF binding to SRE 6.9 in the Arc promoter is essential for LTD in cultured Purkinje cells.
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ABSTRACT: It has been suggested that gene expression and protein synthesis are required for both long-term memory consolidation and late phases of long-term potentiation and long-term depression (LTD). The necessary genes and the specific transcription factor binding sites in their promoters remain unknown. We found that inhibition of the transcription factor SRF or its cofactor MAL blocked the late phase of LTD in mouse cultured cerebellar Purkinje cells, as did deletion of the immediate early gene Arc. Using neuronal bacterial artificial chromosome (BAC) transfection, we found that, in Arc-/- cells transfected with a wild-type Arc BAC, late-phase LTD was rescued. However, mutation of one SRF-binding site in the Arc promoter (SRE 6.9) blocked this rescue. Co-transfection of wild-type Arc and SRF engineered to bind mutated SRE 6.9 restored late-phase LTD in Arc-/-, SRE 6.9 mutant BAC cells. Thus, SRF binding to SRE 6.9 in the Arc promoter is required for the late phase of cerebellar LTD.Nature Neuroscience 09/2010; 13(9):1082-9. · 15.53 Impact Factor -
Article: Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons.
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ABSTRACT: Homeostatic synaptic scaling alters the strength of synapses to compensate for prolonged changes in network activity and involves both excitatory and inhibitory neurons. The immediate-early gene Narp (neuronal activity-regulated pentraxin) encodes a secreted synaptic protein that can bind to and induce clustering of AMPA receptors (AMPARs). We found that Narp prominently accumulated at excitatory synapses on parvalbumin-expressing interneurons (PV-INs). Increasing network activity resulted in a homeostatic increase of excitatory synaptic strength onto PV-INs that increased inhibitory drive and this response was absent in neurons cultured from Narp-/- mice. Activity-dependent changes in the strength of excitatory inputs on PV-INs in acute hippocampal slices were also dependent on Narp and Narp-/- mice had increased sensitivity to kindling-induced seizures. We propose that Narp recruits AMPARs at excitatory synapses onto PV-INs to rebalance network excitation/inhibition dynamics following episodes of increased circuit activity.Nature Neuroscience 09/2010; 13(9):1090-7. · 15.53 Impact Factor -
Article: Journal of Neurophysiology and the Neuroscience Peer Review Consortium (NPRC).
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ABSTRACT: none.Journal of Neurophysiology 02/2010; · 3.32 Impact Factor -
Article: Calcium influx measured at single presynaptic boutons of cerebellar granule cell ascending axons and parallel fibers.
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ABSTRACT: Action potential-evoked calcium influx into presynaptic boutons is a key determinant of synaptic strength and function. Here, we have examined the calcium dynamics at individual presynaptic boutons of the cerebellar granule cells in the molecular layer of cerebellar slices and investigated whether different subpopulations of granule cell boutons exhibit different calcium dynamics. We found that a population of boutons with low basal calcium clearance rates may activate a second clearance mechanism and exhibit biphasic calcium decay on high calcium influx induced by bursts of action potentials. We also found that boutons on ascending axons and parallel fibers show similar calcium influx amplitudes and calcium clearance rates in response to action potentials. Lastly, we found that parallel fiber boutons located in the inner molecular layer have a higher calcium clearance rate than boutons located in the outer molecular layer. These results suggest that cerebellar granule cell boutons should not be regarded as a homogeneous population, but rather that different subpopulations of boutons may exhibit different properties. The heterogeneity of presynaptic boutons may allow different learned behaviors to be encoded in the same circuit without mutual interference and may be a general mechanism for increasing the computational capacity of the brain.The Cerebellum 01/2010; 11(1):121-31. · 3.21 Impact Factor -
Article: Neuromodulation at single presynaptic boutons of cerebellar parallel fibers is determined by bouton size and basal action potential-evoked Ca transient amplitude.
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ABSTRACT: Most presynaptic terminals in the brain contain G-protein-coupled receptors that function to reduce action potential-evoked neurotransmitter release. These neuromodulatory receptors, including those for glutamate, GABA, endocannabinoids, and adenosine, exert a substantial portion of their effect by reducing evoked presynaptic Ca(2+) transients. Many axons form synapses with multiple postsynaptic neurons, but it is unclear whether presynaptic attenuation in these synapses is homogeneous, as suggested by population-level Ca(2+) imaging. We loaded Ca(2+)-sensitive dyes into cerebellar parallel fiber axons and imaged action potential-evoked Ca(2+) transients in individual presynaptic boutons with application of three different neuromodulators and found that adjacent boutons on the same axon showed striking heterogeneity in their strength of attenuation. Moreover, attenuation was predicted by bouton size or basal Ca(2+) response: smaller boutons were more sensitive to adenosine A1 agonist but less sensitive to CB1 agonist, while boutons with high basal action potential-evoked Ca(2+) transient amplitude were more sensitive to mGluR4 agonist. These results suggest that boutons within brief segment of a single parallel fiber axon can have different sensitivities toward neuromodulators and may have different capacities for both short-term and long-term plasticities.Journal of Neuroscience 12/2009; 29(49):15586-94. · 7.11 Impact Factor -
Article: Preprint Servers and the Journal of Neurophysiology.
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ABSTRACT: None.Journal of Neurophysiology 10/2009; · 3.32 Impact Factor -
Article: Dopamine signaling is required for depolarization-induced slow current in cerebellar Purkinje cells.
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ABSTRACT: Brief strong depolarization of cerebellar Purkinje cells produces a slow inward cation current. This current, called depolarization-induced slow current (DISC), is triggered by Ca influx in the Purkinje cell and is attenuated by a blocker of vesicular fusion. Previous work in other brain regions, such as the substantia nigra and ventral tegmental area, has shown that dopamine can be released from dendrites to produce paracrine and autocrine signaling. Here, we test the hypothesis that postsynaptic release of dopamine and autocrine activation of dopamine receptors is involved in DISC. Light immunohistochemistry showed that D(3) dopamine receptors, vesicular monoamine transporter type 2 (VMAT2), and dopamine plasma membrane transporters (DATs) were all expressed in cerebellar Purkinje cells. However, their expression was strongest in the gyrus region of cerebellar lobules IX and X. Comparison of DISC across lobules revealed that it was weak in the anterior portions of the cerebellum (lobules II, V, and VI) and strong in lobules IX and X. DISC was blocked by dopamine receptor antagonists (haloperidol, clozapine, eticlopride, and SCH23390). Likewise, DISC was strongly attenuated by inhibitors of VMAT (reserpine and tetrabenazine) and DAT (GBR12909 and rimcazole). These drugs did not produce DISC attenuation through blockade of depolarization-evoked Purkinje cell Ca transients. Purkinje cells in cerebellar slices derived from DAT-null mice expressed DISC, but this DISC ran down at a significantly higher rate than littermate controls. Together, these results suggest that strong Purkinje cell depolarization produces Ca-dependent release of vesicular postsynaptic dopamine that then excites Purkinje cells in an autocrine manner.Journal of Neuroscience 08/2009; 29(26):8530-8. · 7.11 Impact Factor -
Article: Is there gender bias in the peer review process at Journal of Neurophysiology?
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ABSTRACT: no abstract.Journal of Neurophysiology 04/2009; · 3.32 Impact Factor -
Article: Depolarization-induced slow current in cerebellar Purkinje cells does not require metabotropic glutamate receptor 1.
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ABSTRACT: Activation of cerebellar Purkinje cells by either brief depolarizing steps or bursts of climbing fiber synaptic activation evokes a slow inward current, which we have previously called depolarization-induced slow current or DISC. DISC is triggered by Ca influx via voltage-sensitive Ca channels and is attenuated by inhibitors of vacuolar ATPase or vesicle fusion. This led us to suggest that DISC required vesicular release of glutamate from the somatodendritic region of Purkinje cells. Furthermore, we found that DISC was attenuated by the mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), indicating that DISC required autocrine activation of metabotropic glutamate receptor 1 (mGluR1). Here, we have revisited the role of mGluR1 and found that it is, in fact, not required for DISC. CPCCOEt, but not three other specific mGluR1 antagonists (JNJ16259685, alpha-amino-5-carboxy-3-methyl-2-thiopheneacetic acid (3-MATIDA), Bay 36-7620), attenuated DISC, even though all four of these drugs produced near-complete blockade of current evoked by puffs of the exogenous mGluR1/5 agonist DHPG. Cerebellar slices derived from mGluR1 null mice showed substantial DISC that was still attenuated by CPCCOEt. mGluR5 is functionally similar to mGluR1, but is not expressed at high levels in cerebellar Purkinje cells. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), an mGluR5 antagonist, did not attenuate DISC, and DISC was still present in Purkinje cells derived from mGluR1/mGluR5 double null mice. Thus, neither mGluR1 nor mGluR5 is required for DISC in cerebellar Purkinje cells.Neuroscience 02/2009; 162(3):688-93. · 3.38 Impact Factor -
Article: Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD.
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ABSTRACT: Group I metabotropic glutamate receptors (mGluR) induce long-term depression (LTD) that requires protein synthesis. Here, we demonstrate that Arc/Arg3.1 is translationally induced within 5 min of mGluR activation, and this response is essential for mGluR-dependent LTD. The increase in Arc/Arg3.1 translation requires eEF2K, a Ca(2+)/calmodulin-dependent kinase that binds mGluR and dissociates upon mGluR activation, whereupon it phosphorylates eEF2. Phospho-eEF2 acts to slow the elongation step of translation and inhibits general protein synthesis but simultaneously increases Arc/Arg3.1 translation. Genetic deletion of eEF2K results in a selective deficit of rapid mGluR-dependent Arc/Arg3.1 translation and mGluR-LTD. This rapid translational mechanism is disrupted in the fragile X disease mouse (Fmr1 KO) in which mGluR-LTD does not require de novo protein synthesis but does require Arc/Arg3.1. We propose a model in which eEF2K-eEF2 and FMRP coordinately control the dynamic translation of Arc/Arg3.1 mRNA in dendrites that is critical for synapse-specific LTD.Neuron 08/2008; 59(1):70-83. · 14.74 Impact Factor -
Article: The glutamate receptor-interacting protein family of GluR2-binding proteins is required for long-term synaptic depression expression in cerebellar Purkinje cells.
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ABSTRACT: Glutamate receptor-interacting protein 1 (GRIP1) and GRIP2 are closely related proteins that bind GluR2-containing AMPA receptors and couple them to structural and signaling complexes in neurons. Cerebellar long-term synaptic depression (LTD) is a model system of synaptic plasticity that is expressed by persistent internalization of GluR2-containing AMPA receptors. Here, we show that genetic deletion of both GRIP1 and GRIP2 blocks LTD expression in primary cultures of mouse cerebellar neurons but that single deletion of either isoform allows LTD to occur. In GRIP1/2 double knock-out Purkinje cells, LTD can be fully rescued by a plasmid-driving expression of GRIP1 and partially rescued by a GRIP2 plasmid. These results indicate that the GRIP family comprises an essential molecular component for cerebellar LTD.Journal of Neuroscience 06/2008; 28(22):5752-5. · 7.11 Impact Factor -
Article: Transient upregulation of postsynaptic IP3-gated Ca release underlies short-term potentiation of metabotropic glutamate receptor 1 signaling in cerebellar Purkinje cells.
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ABSTRACT: Synaptic plasticity lasting approximately 100 s has been suggested to function as a temporary buffer for neural information. One example of this was reported by Batchelor and Garthwaite (1997), who found that a slow metabotropic glutamate receptor 1 (mGluR1)-evoked EPSP produced by burst stimulation of cerebellar parallel fiber-Purkinje cell synapses could be potentiated by a conditioning stimulus consisting of prior activation of climbing fiber synapses (or injection of depolarizing current) with a delay of up to 90 s. What is the molecular basis of the signal that spans this temporal gap? Here, we show that mGluR1-evoked slow EPSCs evoked by parallel fiber burst test stimuli show a similar form of short-term potentiation (mGluR1-STP) and that this phenomenon is also observed when parallel fiber bursts are replaced by pressure pulses of an exogenous mGluR1 agonist. Ca imaging experiments revealed that cytosolic Ca levels returned to baseline within several seconds after conditioning depolarization, indicating that this cannot underlie mGluR1-STP. To test the hypothesis that transient upregulation of inositol-1,4,5-trisphosphate (IP(3))-gated Ca release underlies this phenomenon, we used local photolytic uncaging of IP(3) to deplete IP(3)-gated Ca stores. IP(3) uncaging in the interval between conditioning depolarization and the test pulse produced a complete blockade of mGluR1-STP, as did blockade of IP(3) receptors with heparin. When Ca transients evoked by IP(3) uncaging were used as a test stimulus, conditioning depolarization produced a large STP of Ca response amplitudes. These data suggest that transient upregulation of postsynaptic IP(3)-gated Ca signaling constitutes a novel form of short-term synaptic plasticity.Journal of Neuroscience 05/2008; 28(17):4350-5. · 7.11 Impact Factor -
Article: mGluR1/5-dependent long-term depression requires the regulated ectodomain cleavage of neuronal pentraxin NPR by TACE.
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ABSTRACT: Matrix metalloproteases (MMPs) play a role in remodeling the extracellular matrix during brain development and have been implicated in synaptic plasticity. Here, we report that a member of the neuronal pentraxin (NP) family, neuronal pentraxin receptor (NPR), undergoes regulated cleavage by the MMP tumor necrosis factor-alpha converting enzyme (TACE). NPR is enriched at excitatory synapses where it associates with AMPA-type glutamate receptors (AMPAR) and enhances synaptogenesis. However, in response to activation of group 1 mGluRs (mGluR1/5), TACE cleaves NPR and releases the pentraxin domain from its N-terminal transmembrane domain. Cleaved NPR rapidly accumulates in endosomes where it colocalizes with AMPAR. This process is necessary for mGluR1/5-dependent LTD in hippocampal and cerebellar synapses. These observations suggest that cleaved NPR functions to "capture" AMPAR for endocytosis and reveal a bifunctional role of NPs in both synapse strengthening and weakening.Neuron 04/2008; 57(6):858-71. · 14.74 Impact Factor
Top co-authors
Top Journals
- Neuron (7)
- Journal of Neuroscience (6)
- Neuron (4)
- Nature Neuroscience (4)
- Journal of Neurophysiology (4)
Institutions
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2002–2011
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Johns Hopkins University
- • Department of Neuoscience
- • Department of Neurosurgery
Baltimore, MD, USA
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2007–2008
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Seoul National University Hospital
Seoul, Seoul, South Korea
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2003–2005
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Howard Hughes Medical Institute
Chevy Chase, MD, USA
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