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49 Publications

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    Magee Lab
    02/01/04 | LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites.
    Frick A, Magee J, Johnston D
    Nature Neuroscience. 2004 Feb;7(2):126-35. doi: 10.1002/cbic.201000254

    The propagation and integration of signals in the dendrites of pyramidal neurons is regulated, in part, by the distribution and biophysical properties of voltage-gated ion channels. It is thus possible that any modification of these channels in a specific part of the dendritic tree might locally alter these signaling processes. Using dendritic and somatic whole-cell recordings, combined with calcium imaging in rat hippocampal slices, we found that the induction of long-term potentiation (LTP) was accompanied by a local increase in dendritic excitability that was dependent on the activation of NMDA receptors. These changes favored the back-propagation of action potentials into this dendritic region with a subsequent boost in the Ca(2+) influx. Dendritic cell-attached patch recordings revealed a hyperpolarized shift in the inactivation curve of transient, A-type K(+) currents that can account for the enhanced excitability. These results suggest an important mechanism associated with LTP for shaping signal processing and controlling dendritic function.

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    Magee Lab
    10/22/03 | Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons.
    McDermott CM, LaHoste GJ, Chen C, Musto A, Bazan NG, Magee JC
    The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2003 Oct 22;23(29):9687-95. doi: 10.1002/cbic.201000254

    Although the function of sleep remains elusive, several lines of evidence suggest that sleep has an important role in learning and memory. In light of the available data and with the prevalence of sleep deprivation (SD), we sought to determine the effect of SD on neuronal functioning. We found that the exposure of rats to 72 hr of primarily rapid eye movement SD impaired their subsequent performance on a hippocampus-dependent spatial learning task but had no effect on an amygdala-dependent learning task. To determine the underlying cellular level mechanisms of this hippocampal deficit, we examined the impact of SD on several fundamental aspects of membrane excitability and synaptic physiology in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. We found that neuronal excitability was severely reduced in CA1 neurons but not in granule cells and that the production of long-term potentiation of synaptic strength was inhibited in both areas. Using multiple SD methods we further attempted to differentiate the effects of sleep deprivation from those associated with the nonspecific stress induced by the sleep deprivation methods. Together these data suggest that failure to acquire adequate sleep produces several molecular and cellular level alterations that profoundly inhibit hippocampal functioning.

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    Magee Lab
    10/01/03 | Impaired regulation of synaptic strength in hippocampal neurons from GluR1-deficient mice.
    Andrasfalvy BK, Smith MA, Borchardt T, Sprengel R, Magee JC
    The Journal of Physiology. 2003 Oct 1;552(Pt 1):35-45. doi: 10.1002/cbic.201000254

    Neurons of the central nervous system (CNS) exhibit a variety of forms of synaptic plasticity, including associative long-term potentiation and depression (LTP/D), homeostatic activity-dependent scaling and distance-dependent scaling. Regulation of synaptic neurotransmitter receptors is currently thought to be a common mechanism amongst many of these forms of plasticity. In fact, glutamate receptor 1 (GluR1 or GluRA) subunits containing L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors have been shown to be required for several forms of hippocampal LTP and a particular hippocampal-dependent learning task. Because of this importance in associative plasticity, we sought to examine the role of these receptors in other forms of synaptic plasticity in the hippocampus. To do so, we recorded from the apical dendrites of hippocampal CA1 pyramidal neurons in mice lacking the GluR1 subunit (GluR1 -/-). Here we report data from outside-out patches that indicate GluR1-containing receptors are essential to the extrasynaptic population of AMPA receptors, as this pool was nearly empty in the GluR1 -/- mice. Additionally, these receptors appear to be a significant component of the synaptic glutamate receptor pool because the amplitude of spontaneous synaptic currents recorded at the site of input and synaptic AMPA receptor currents evoked by focal glutamate uncaging were both substantially reduced in these mice. Interestingly, the impact on synaptic weight was greatest at distant synapses such that the normal distance-dependent synaptic scaling used by these cells to counter dendritic attenuation was lacking in GluR1 -/- mice. Together the data suggest that the highly regulated movement of GluR1-containing AMPA receptors between extrasynaptic and synaptic receptor pools is critically involved in establishing two functionally diverse forms of synaptic plasticity: LTP and distance-dependent scaling.

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    Magee Lab
    04/15/03 | Normalization of Ca2+ signals by small oblique dendrites of CA1 pyramidal neurons.
    Frick A, Magee J, Koester HJ, Migliore M, Johnston D
    The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2003 Apr 15;23(8):3243-50. doi: 10.1002/cbic.201000254

    Oblique dendrites of CA1 pyramidal neurons predominate in stratum radiatum and receive approximately 80% of the synaptic input from Schaffer collaterals. Despite this fact, most of our understanding of dendritic signal processing in these neurons comes from studies of the main apical dendrite. Using a combination of Ca2+ imaging and whole-cell recording techniques in rat hippocampal slices, we found that the properties of the oblique dendrites differ markedly from those of the main dendrites. These different properties tend to equalize the Ca2+ rise from single action potentials as they backpropagate into the oblique dendrites from the main trunk. Evidence suggests that this normalization of Ca2+ signals results from a higher density of a transient, A-type K+ current [I(K(A))] in the oblique versus the main dendrites. The higher density of I(K(A)) may have important implications for our understanding of synaptic integration and plasticity in these structures.

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    Magee Lab
    04/01/03 | Mechanism of the distance-dependent scaling of Schaffer collateral synapses in rat CA1 pyramidal neurons.
    Smith MA, Ellis-Davies GC, Magee JC
    The Journal of Physiology. 2003 Apr 1;548(Pt 1):245-58. doi: 10.1002/cbic.201000254

    Schaffer collateral axons form excitatory synapses that are distributed across much of the dendritic arborization of hippocampal CA1 pyramidal neurons. Remarkably, AMPA-receptor-mediated miniature EPSP amplitudes at the soma are relatively independent of synapse location, despite widely different degrees of dendritic filtering. A progressive increase with distance in synaptic conductance is thought to produce this amplitude normalization. In this study we examined the mechanism(s) responsible for spatial scaling by making whole-cell recordings from the apical dendrites of CA1 pyramidal neurons. We found no evidence to suggest that there is any location dependence to the range of cleft glutamate concentrations found at Schaffer collateral synapses. Furthermore, we observed that release probability (Pr), paired-pulse facilitation and the size of the readily releasable vesicular pool are not dependent on synapse location. Thus, there do not appear to be any changes in the fundamental presynaptic properties of Schaffer collateral synapses that could account for distance-dependent scaling. On the other hand, two-photon uncaging of 4-methoxy-7-nitroindolinyl-caged L-glutamate onto isolated dendritic spines shows that the number of postsynaptic AMPA receptors per spine increases with distance from the soma. We conclude, therefore, that the main synaptic mechanism involved in the production of distance-dependent scaling of Schaffer collateral synapses is an elevated postsynaptic AMPA receptor density.

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    Magee Lab
    03/01/03 | Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation.
    Magee JA, Abdulkadir SA, Milbrandt J
    Cancer Cell. 2003 Mar;3(3):273-83. doi: 10.1002/cbic.201000254

    Tumorigenesis requires sequential accumulation of multiple genetic lesions. In the prostate, tumor initiation is often linked to loss of heterozygosity at the Nkx3.1 locus. In mice, loss of even one Nkx3.1 allele causes prostatic epithelial hyperplasia and eventual prostatic intraepithelial neoplasia (PIN) formation. Here we demonstrate that Nkx3.1 allelic loss extends the proliferative stage of regenerating luminal cells, leading to epithelial hyperplasia. Microarray analysis identified Nkx3.1 target genes, many of which show exquisite dosage sensitivity. The number of Nkx3.1 alleles determines the relative probabilities of stochastic activation or inactivation of a given target gene. Thus, loss of a single Nkx3.1 allele likely results in hyperplasia and PIN by increasing the probability of completely inactivating select Nkx3.1-regulated pathways within a subset of affected cells.

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    Magee Lab
    01/01/03 | A prominent role for intrinsic neuronal properties in temporal coding.
    Magee JC
    Trends in Neurosciences. 2003 Jan;26(1):14-6. doi: 10.1002/cbic.201000254

    A recent report presents evidence that the exact timing of action potential output in rat hippocampal pyramidal neurons is similarly modulated during several diverse forms of behavior. These data suggest that it is, to a large degree, the intrinsic properties of the neurons themselves that produce this temporal coding of information. Thus, this report provides an outstanding example of the importance of single neuronal properties, even during complex behaviors.

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    Magee Lab
    06/15/02 | Phosphorylation-dependent differences in the activation properties of distal and proximal dendritic Na+ channels in rat CA1 hippocampal neurons.
    Gasparini S, Magee JC
    The Journal of Physiology. 2002 Jun 15;541(Pt 3):665-72. doi: 10.1002/cbic.201000254

    {At distal dendritic locations, the threshold for action potential generation is higher and the amplitude of back-propagating spikes is decreased. To study whether these characteristics depend upon Na+ channels, their voltage-dependent properties at proximal and distal dendritic locations were compared in CA1 hippocampal neurons. Distal Na+ channels activated at more hyperpolarized voltages than proximal (half-activation voltages were -20.4 +/- 2.4 mV vs. -12.0 +/- 1.7 mV for distal and proximal patches, respectively

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    Magee Lab
    03/01/02 | Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia.
    Abdulkadir SA, Magee JA, Peters TJ, Kaleem Z, Naughton CK, Humphrey PA, Milbrandt J
    Molecular and Cellular Biology. 2002 Mar;22(5):1495-503. doi: 10.1002/cbic.201000254

    The homeodomain-containing transcription factor NKX3.1 is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3.1 protein expression is common in human prostate carcinomas and prostatic intraepithelial neoplasia (PIN) lesions and correlates with tumor progression. Disruption of the murine Nkx3.1 gene results in defects in prostate branching morphogenesis, secretions, and growth. To more closely mimic the pattern of NKX3.1 loss that occurs in human prostate tumors, we have used Cre- and loxP-mediated recombination to delete the Nkx3.1 gene in the prostates of adult transgenic mice. Conditional deletion of one or both alleles of Nkx3.1 leads to the development of preinvasive lesions that resemble PIN. The pattern of expression of several biomarkers (Ki-67, E-cadherin, and high-molecular-weight cytokeratins) in these PIN lesions resembled that observed in human cases of PIN. Furthermore, PIN foci in mice with conditional deletion of a single Nkx3.1 allele lose expression of the wild-type allele. Our results support the role of NKX3.1 as a prostate tumor suppressor and indicate a role for this gene in tumor initiation.

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