Main Menu (Mobile)- Block

Main Menu - Block

janelia7_blocks-janelia7_fake_breadcrumb | block
Lee Tzumin Lab / Publications
custom | custom

Filter

facetapi-Q2b17qCsTdECvJIqZJgYMaGsr8vANl1n | block

Associated Lab

facetapi-PV5lg7xuz68EAY8eakJzrcmwtdGEnxR0 | block
facetapi-021SKYQnqXW6ODq5W5dPAFEDBaEJubhN | block

Type of Publication

general_search_page-panel_pane_1 | views_panes

12 Publications

Showing 1-10 of 12 results
Your Criteria:
    02/01/09 | Stochastically gating ion channels enable patterned spike firing through activity-dependent modulation of spike probability.
    Dudman JT, Nolan MF
    PLoS Computational Biology. 2009 Feb;5(2):e1000290. doi: 10.3389/fnana.2010.00147

    The transformation of synaptic input into patterns of spike output is a fundamental operation that is determined by the particular complement of ion channels that a neuron expresses. Although it is well established that individual ion channel proteins make stochastic transitions between conducting and non-conducting states, most models of synaptic integration are deterministic, and relatively little is known about the functional consequences of interactions between stochastically gating ion channels. Here, we show that a model of stellate neurons from layer II of the medial entorhinal cortex implemented with either stochastic or deterministically gating ion channels can reproduce the resting membrane properties of stellate neurons, but only the stochastic version of the model can fully account for perithreshold membrane potential fluctuations and clustered patterns of spike output that are recorded from stellate neurons during depolarized states. We demonstrate that the stochastic model implements an example of a general mechanism for patterning of neuronal output through activity-dependent changes in the probability of spike firing. Unlike deterministic mechanisms that generate spike patterns through slow changes in the state of model parameters, this general stochastic mechanism does not require retention of information beyond the duration of a single spike and its associated afterhyperpolarization. Instead, clustered patterns of spikes emerge in the stochastic model of stellate neurons as a result of a transient increase in firing probability driven by activation of HCN channels during recovery from the spike afterhyperpolarization. Using this model, we infer conditions in which stochastic ion channel gating may influence firing patterns in vivo and predict consequences of modifications of HCN channel function for in vivo firing patterns.

    View Publication Page
    12/20/07 | HCN1 channels constrain synaptically evoked Ca2+ spikes in distal dendrites of CA1 pyramidal neurons.
    Tsay D, Dudman JT, Siegelbaum SA
    Neuron. 2007 Dec 20;56(6):1076-89. doi: 10.1016/j.neuron.2007.11.015

    HCN1 hyperpolarization-activated cation channels act as an inhibitory constraint of both spatial learning and synaptic integration and long-term plasticity in the distal dendrites of hippocampal CA1 pyramidal neurons. However, as HCN1 channels provide an excitatory current, the mechanism of their inhibitory action remains unclear. Here we report that HCN1 channels also constrain CA1 distal dendritic Ca2+ spikes, which have been implicated in the induction of LTP at distal excitatory synapses. Our experimental and computational results indicate that HCN1 channels provide both an active shunt conductance that decreases the temporal integration of distal EPSPs and a tonic depolarizing current that increases resting inactivation of T-type and N-type voltage-gated Ca2+ channels, which contribute to the Ca2+ spikes. This dual mechanism may provide a general means by which HCN channels regulate dendritic excitability.

    View Publication Page
    12/06/07 | A role for synaptic inputs at distal dendrites: instructive signals for hippocampal long-term plasticity.
    Dudman JT, Tsay D, Siegelbaum SA
    Neuron. 2007 Dec 6;56(5):866-79. doi: 10.1016/j.neuron.2007.10.020

    Synaptic potentials originating at distal dendritic locations are severely attenuated when they reach the soma and, thus, are poor at driving somatic spikes. Nonetheless, distal inputs convey essential information, suggesting that such inputs may be important for compartmentalized dendritic signaling. Here we report a new plasticity rule in which stimulation of distal perforant path inputs to hippocampal CA1 pyramidal neurons induces long-term potentiation at the CA1 proximal Schaffer collateral synapses when the two inputs are paired at a precise interval. This subthreshold form of heterosynaptic plasticity occurs in the absence of somatic spiking but requires activation of both NMDA receptors and IP(3) receptor-dependent release of Ca(2+) from internal stores. Our results suggest that direct sensory information arriving at distal CA1 synapses through the perforant path provide compartmentalized, instructive signals that assess the saliency of mnemonic information propagated through the hippocampal circuit to proximal synapses.

    View Publication Page
    11/14/07 | HCN1 channels control resting and active integrative properties of stellate cells from layer II of the entorhinal cortex.
    Nolan MF, Dudman JT, Dodson PD, Santoro B
    The Journal of Neuroscience. 2007 Nov 14;27(46):12440-51. doi: 10.1523/JNEUROSCI.2358-07.2007

    Whereas recent studies have elucidated principles for representation of information within the entorhinal cortex, less is known about the molecular basis for information processing by entorhinal neurons. The HCN1 gene encodes ion channels that mediate hyperpolarization-activated currents (I(h)) that control synaptic integration and influence several forms of learning and memory. We asked whether hyperpolarization-activated, cation nonselective 1 (HCN1) channels control processing of information by stellate cells found within layer II of the entorhinal cortex. Axonal projections from these neurons form a major component of the synaptic input to the dentate gyrus of the hippocampus. To determine whether HCN1 channels control either the resting or the active properties of stellate neurons, we performed whole-cell recordings in horizontal brain slices prepared from adult wild-type and HCN1 knock-out mice. We found that HCN1 channels are required for rapid and full activation of hyperpolarization-activated currents in stellate neurons. HCN1 channels dominate the membrane conductance at rest, are not required for theta frequency (4-12 Hz) membrane potential fluctuations, but suppress low-frequency (<4 Hz) components of spontaneous and evoked membrane potential activity. During sustained activation of stellate cells sufficient for firing of repeated action potentials, HCN1 channels control the pattern of spike output by promoting recovery of the spike afterhyperpolarization. These data suggest that HCN1 channels expressed by stellate neurons in layer II of the entorhinal cortex are key molecular components in the processing of inputs to the hippocampal dentate gyrus, with distinct integrative roles during resting and active states.

    View Publication Page
    03/02/06 | Making the grade with models of persistent activity.
    Dudman JT, Siegelbaum SA
    Neuron. 2006 Mar 2;49(5):649-51. doi: 10.3389/fnana.2010.00147

    Persistent neural activity that outlasts an initial stimulus is thought to provide a mechanism for the transient storage of memory. In this issue of Neuron, Fransén et al. identify important principles for a cell-autonomous mechanism of graded persistent firing using an elegant combination of experimental and computational approaches.

    View Publication Page
    09/28/05 | Mechanism of positive allosteric modulators acting on AMPA receptors.
    Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM
    The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2005 Sep 28;25(39):9027-36. doi: 10.3389/fnana.2010.00147

    Ligand-gated ion channels involved in the modulation of synaptic strength are the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate AMPA receptor currents relieve cognitive deficits caused by neurodegenerative diseases such as Alzheimer’s disease and show promise in the treatment of depression. Previously, there has been limited understanding of the molecular mechanism of action for AMPA receptor potentiators. Here we present cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614 (pyrrolidino-1,3-oxazino benzo-1,4-dioxan-10-one), two AMPA receptor potentiators that preferentially slow AMPA receptor deactivation. Both potentiators bind within the dimer interface of the nondesensitized receptor at a common site located on the twofold axis of molecular symmetry. Importantly, the potentiator binding site is adjacent to the "hinge" in the ligand-binding core "clamshell" that undergoes conformational rearrangement after glutamate binding. Using rapid solution exchange, patch-clamp electrophysiology experiments, we show that point mutations of residues that interact with potentiators in the cocrystal disrupt potentiator function. We suggest that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation.

    View Publication Page
    05/01/05 | Antipsychotic drugs elevate mRNA levels of presynaptic proteins in the frontal cortex of the rat.
    MacDonald ML, Eaton ME, Dudman JT, Konradi C
    Biological Psychiatry. 2005 May 1;57(9):1041-51. doi: 10.3389/fnana.2010.00147

    Molecular adaptations are believed to contribute to the mechanism of action of antipsychotic drugs (APDs). We attempted to establish common gene regulation patterns induced by chronic treatment with APDs.

    View Publication Page
    12/16/04 | Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces.
    Etkin A, Klemenhagen KC, Dudman JT, Rogan MT, Hen R, Kandel ER, Hirsch J
    Neuron. 2004 Dec 16;44(6):1043-55. doi: 10.3389/fnana.2010.00147

    Responses to threat-related stimuli are influenced by conscious and unconscious processes, but the neural systems underlying these processes and their relationship to anxiety have not been clearly delineated. Using fMRI, we investigated the neural responses associated with the conscious and unconscious (backwardly masked) perception of fearful faces in healthy volunteers who varied in threat sensitivity (Spielberger trait anxiety scale). Unconscious processing modulated activity only in the basolateral subregion of the amygdala, while conscious processing modulated activity only in the dorsal amygdala (containing the central nucleus). Whereas activation of the dorsal amygdala by conscious stimuli was consistent across subjects and independent of trait anxiety, activity in the basolateral amygdala to unconscious stimuli, and subjects’ reaction times, were predicted by individual differences in trait anxiety. These findings provide a biological basis for the unconscious emotional vigilance characteristic of anxiety and a means for investigating the mechanisms and efficacy of treatments for anxiety.

    View Publication Page
    11/24/04 | L-type Ca2+ channel blockers promote Ca2+ accumulation when dopamine receptors are activated in striatal neurons.
    Eaton ME, Macías W, Youngs RM, Rajadhyaksha A, Dudman JT, Konradi C
    Brain Research. Molecular Brain Research. 2004 Nov 24;131(1-2):65-72. doi: 10.3389/fnana.2010.00147

    Dopamine (DA) receptor-mediated signal transduction and gene expression play a central role in many brain disorders from schizophrenia to Parkinson’s disease to addiction. While trying to evaluate the role of L-type Ca2+ channels in dopamine D1 receptor-mediated phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB), we found that activation of dopamine D1 receptors alters the properties of L-type Ca2+ channel inhibitors and turns them into facilitators of Ca2+ influx. In D1 receptor-stimulated neurons, L-type Ca2+ channel blockers promote cytosolic Ca2+ accumulation. This leads to the activation of a molecular signal transduction pathway and CREB phosphorylation. In the absence of dopamine receptor stimulation, L-type Ca2+ channel blockers inhibit CREB phosphorylation. The effect of dopamine on L-type Ca2+ channel blockers is dependent on protein kinase A (PKA), suggesting that protein phosphorylation plays a role in this phenomenon. Because of the adverse effect of activated dopamine receptors on L-type Ca2+ channel blocker action, the role of L-type Ca2+ channels in the dopamine D1 receptor signal transduction pathway cannot be assessed with pharmacological tools. However, with antisense technology, we demonstrate that L-type Ca2+ channels contribute to D1 receptor-mediated CREB phosphorylation. We conclude that the D1 receptor signal transduction pathway depends on L-type Ca2+ channels to mediate CREB phosphorylation.

    View Publication Page
    11/26/03 | The hyperpolarization-activated HCN1 channel is important for motor learning and neuronal integration by cerebellar Purkinje cells.
    Nolan MF, Malleret G, Lee KH, Gibbs E, Dudman JT, Santoro B, Yin D, Thompson RF, Siegelbaum SA, Kandel ER, Morozov A
    Cell. 2003 Nov 26;115(5):551-64. doi: 10.3389/fnana.2010.00147

    In contrast to our increasingly detailed understanding of how synaptic plasticity provides a cellular substrate for learning and memory, it is less clear how a neuron’s voltage-gated ion channels interact with plastic changes in synaptic strength to influence behavior. We find, using generalized and regional knockout mice, that deletion of the HCN1 channel causes profound motor learning and memory deficits in swimming and rotarod tasks. In cerebellar Purkinje cells, which are a key component of the cerebellar circuit for learning of correctly timed movements, HCN1 mediates an inward current that stabilizes the integrative properties of Purkinje cells and ensures that their input-output function is independent of the previous history of their activity. We suggest that this nonsynaptic integrative function of HCN1 is required for accurate decoding of input patterns and thereby enables synaptic plasticity to appropriately influence the performance of motor activity.

    View Publication Page