Biomedical subjects

John R Clay

Publications and source records attributed to John R Clay.

5 recordsLinked to original sources

PubMed2006

Noisy inputs and the induction of on-off switching behavior in a neuronal pacemaker.

Neuronal oscillators can function as bistable toggle switches, flipping between quiescence and rhythmic firing in response to an input stimulus. In theory, such switching should be sensitive to small noisy inputs if the bistable states are in close proximity, which we test here using a perfused squid axon preparation. We find that small noisy stimulus currents induce a multitude of paths between two nearby stable states: repetitive firing and quiescence. The pattern of on-off switching of the pacemaker depends on the intensity, spectral properties, and phase angle of stimulus current fluctuations. Analysis by spike-triggered averaging of the stimulus currents near the transitions reveals that sinusoidal stimuli timed antiphase or in phase with repetitive firing correlates with switching of the pacemaker off or on, respectively. Our results reveal a distinct form of bistability in which noise can either silence pacemaker activity, trigger repetitive firing, or induce sporadic burst patterns similar to those recorded in a variety of normal and pathological neurons.

Algorithms↗

PubMed2005

Axonal excitability revisited.

The original papers of Hodgkin and Huxley (J. Physiol. 116 (1952a) 449, J. Physiol. 116 (1952b) 473, J. Physiol. 116 (1952c) 497, J. Physiol. 117 (1952d) 500) have provided a benchmark in our understanding of cellular excitability. Not surprisingly, their model of the membrane action potential (AP) requires revisions even for the squid giant axon, the preparation for which it was originally formulated. The mechanisms they proposed for the voltage-gated potassium and sodium ion currents, IK, and INa, respectively, have been superceded by more recent formulations that more accurately describe voltage-clamp measurements of these components. Moreover, the current-voltage relation for IK has a non-linear dependence upon driving force that is well described by the Goldman-Hodgkin-Katz (GHK) relation, rather than the linear dependence on driving force found by Hodgkin and Huxley. Furthermore, accumulation of potassium ions in the extracellular space adjacent to the axolemma appears to be significant even during a single AP. This paper describes the influence of these various modifications in their model on the mathematically reconstructed AP. The GHK and K+ accumulation results alter the shape of the AP, whereas the modifications in IK and INa gating have surprisingly little effect. Perhaps the most significant change in their model concerns the amplitude of INa, which they appear to have overestimated by a factor of two. This modification together with the GHK and the K+ accumulation results largely remove the discrepancies between membrane excitability of the squid giant axon and the Hodgkin and Huxley (J. Physiol. 117 (1952d) 500) model previously described (Clay, J. Neurophysiol. 80 (1998) 903).

Action Potentials↗

PubMed2003

On the persistent sodium current in squid giant axons.

R. F. Rakowski, D. C. Gadsby, and P. DeWeer have reported a persistent, tetrodotoxin-sensitive sodium ion current (I(NaP)) in squid giant axons having a low threshold (-90 mV) and a maximal inward amplitude of -4 microA/cm(2) at -50 mV. This report makes the case that most of I(NaP) is attributable to an ion channel mechanism distinct from the classical rapidly activating and inactivating sodium ion current, I(Na), which is also tetrodotoxin sensitive. The analysis of the contribution of I(Na) to I(NaP) is critically dependent on slow inactivation of I(Na). The results of this gating process reported here demonstrate that inactivation of I(Na) is complete in the steady-state for V > -40 mV, thereby making it unlikely that I(NaP) in this potential range is attributable to I(Na). Moreover, -90 mV is well below I(Na) threshold, as demonstrated by the C. A. Vandenberg and F. Bezanilla model of I(Na) gating in squid giant axons. Their model predicts a persistent current having a threshold of -60 mV and a peak amplitude of -25 microA/cm(2) at -20 mV. Modulation of this component by the slow inactivation process predicts a persistent current that is finite in the -60- to -40-mV range having a peak amplitude of -1 microA/cm(-2) at -50 mV. Subtraction of this current from the I(NaP) measurements yields the portion of I(NaP) that appears to be attributable to an ion channel mechanism distinct from I(Na).

Animals↗

PubMed2002

Trafficking of axonal K+ channels: potential role of Hsc70.

Voltage-gated potassium ion channels in axons underlie the repolarization phase of the membrane action potential and help to set the resting potential. In addition to being present in the axolemma, they are also found in axoplasm in small vesicles, 30-50 nm in diameter, which may serve as a reserve pool of K+ channel protein (Clay and Kuzirian [2000] J Neurobiol 45:172-184). We have developed a novel technique for extracting these vesicles from axoplasm, which relies on the ability of Texas red to bind to them, thereby reducing their buoyancy so that they are amenable to pelleting by ultracentrifugation (Clay and Kuzirian [2000] J Neurobiol 45:172-184). The mechanism underlying this process may be binding of Texas red to Hsc70, which is primarily a cytosolic protein. However, a small portion of it is located on the surface of vesicles. Kinesin is also on the vesicle surface. This protein is membrane bound in our in vitro vesicle preparation when solutions that do not contain MgATP are added to extruded axoplasm. The addition of MgATP to the solution appears to release a significant amount of kinesin from the vesicles, possibly by the Hsc70-MgATP catalysis mechanism recently proposed by Tsai et al.

Animals↗

PubMedDate not supplied

A novel mechanism for irregular firing of a neuron in response to periodic stimulation: irregularity in the absence of noise.

Irregular firing of action potentials (AP's) is a characteristic feature of neurons in the brain. The variability has been attributed to noise from various sources. This study illustrates an alternative mechanism, namely, deterministic irregularity within a model of ionic conductances. Specifically, a model based on modern measurements of the Na+ and K+ current components from the squid giant axon fires irregularly in response to a continuous train of near-threshold current pulses. The interspike interval histogram from these simulations is multi-modal, a result which in other systems has been attributed to stochastic resonance. Moreover, the simulations exhibited short burst of spikes followed by relatively long quiescent periods, a result suggestive of patterned input to the model even though the input consisted of a train of regularly spaced current pulses. The variability of firing is attributable to variations in AP parameters, in particular AP amplitude. The action potential for squid giant axons is not all-or-none. Rather, it is fundamentally a continuous function of stimulus amplitude. That is, the membrane lacks a threshold. Variation in AP amplitude, and to a lesser extent, AP duration, can produce variations in the time to a subsequent AP, which represents a paradigm shift for understanding irregular neuronal firing. The emphasis is not as much on events prior to an AP as it is on the AP's themselves.

Acoustic Stimulation↗