Experimental study of synchronization phenomena under periodic light irradiation of a nonlinear chemical system

A photosensitive chemical oscillating reaction, i.e., the Briggs-Rauscher (B.R.) reaction, exhibiting a wealth of nonlinear behavior, when performed in a continuous-flow stirred-tank reactor, and subjected to periodic light irradiation, is studied as an experimental example of entrainment phenomena observable in biological systems. The adaptation patterns under periodic light irradiation are elucidated by means of the response of the system to continuous and single-pulse light irradiation. It is shown that self-oscillating states, excitable steady states and bistable systems can exhibit the same types of synchronization patterns when submitted to periodic external forces with appropriate amplitude and time scale conditions.     

Modulation of Ca2+-currents by sequential and simultaneous activation of adenosine A1 and A2A receptors in striatal projection neurons

D₁- and D₂-types of dopamine receptors are located separately in direct and indirect pathway striatal projection neurons (dSPNs and iSPNs). In comparison, adenosine A₁-type receptors are located in both neuron classes, and adenosine A_2A-type receptors show a preferential expression in iSPNs. Due to their importance for neuronal excitability, Ca²⁺-currents have been used as final effectors to see the function of signaling cascades associated with different G protein-coupled receptors. For example, among many other actions, D₁-type receptors increase, while D₂-type receptors decrease neuronal excitability by either enhancing or reducing, respectively, Ca_V1 Ca²⁺-currents. These actions occur separately in dSPNs and iSPNs. In the case of purinergic signaling, the actions of A₁- and A_2A-receptors have not been compared observing their actions on Ca²⁺-channels of SPNs as final effectors. Our hypotheses are that modulation of Ca²⁺-currents by A₁-receptors occurs in both dSPNs and iSPNs. In contrast, iSPNs would exhibit modulation by both A₁- and A_2A-receptors. We demonstrate that A₁-type receptors reduced Ca²⁺-currents in all SPNs tested. However, A_2A-type receptors enhanced Ca²⁺-currents only in half tested neurons. Intriguingly, to observe the actions of A_2A-type receptors, occupation of A₁-type receptors had to occur first. However, A₁-receptors decreased Ca_V2 Ca²⁺-currents, while A_2A-type receptors enhanced current through Ca_V1 channels. Because these channels have opposing actions on cell discharge, these differences explain in part why iSPNs may be more excitable than dSPNs. It is demonstrated that intrinsic voltage-gated currents expressed in SPNs are effectors of purinergic signaling that therefore play a role in excitability.     

Excitable Population Dynamics,Biological Control Failure,and Spatiotemporal Pattern Formation in a Model Ecosystem

Biological control has been attracting an increasing attention over the last two decades as an environmentally friendly alternative to the more traditional chemical-based control. In this paper, we address robustness of the biological control strategy with respect to fluctuations in the controlling species density. Specifically, we consider a pest being kept under control by its predator. The predator response is assumed to be of Holling type III, which makes the system’s kinetics “excitable.” The system is studied by means of mathematical modeling and extensive numerical simulations. We show that the system response to perturbations in the predator density can be completely different in spatial and non-spatial systems. In the nonspatial system, an overcritical perturbation of the population density results in a pest outbreak that will eventually decay with time, which can be regarded as a success of the biological control strategy. However, in the spatial system, a similar perturbation can drive the system into a self-sustained regime of spatiotemporal pattern formation with a high pest density, which is clearly a biological control failure. We then identify the parameter range where the biological control can still be successful and describe the corresponding regime of the system dynamics. Finally, we identify the main scenarios of the system response to the population density perturbations and reveal the corresponding structure of the parameter space of the system. A. Morozov is on leave from Shirshov Institute of Oceanology, Russian Academy of Science, Nakhimovsky Prosp. 36, Moscow 117218, Russia.     

Hyperpolarization-activated currents control the excitability of principal neurons in the basolateral amygdala

Anxiety is thought to be influenced by neuronal excitability in basolateral nucleus of the amygdala (BLA). However, molecules that are critical for regulating excitability of BLA neurons are yet to be determined. In the present study, we have examined whether hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which mediate the depolarizing cation current, can control the neuronal excitability. HCN channel-like activity appeared to be detected in BLA principal neurons. ZD7288, a specific blocker for HCN channels, increased the input resistance of membrane, hyperpolarized resting membrane potential, and enhanced action potential firing in BLA principal neurons. The blockade of HCN channels facilitated temporal summation of repetitively evoked excitatory postsynaptic potentials, suggesting that suppression of HCN channel activity in principal neurons can accelerate the propagation of synaptic responses onto the axon hillock. Thus, our findings have laid foundation for studies to reveal how HCN channel activity in BLA principal neurons regulates anxiety in vivo.     

Translational regulation of neuronal electrical properties

The nervous system has an in-built capability to adjust its responsiveness to excitation according to the history of electrical activity faced by the neurons embedded within its networks. This control over excitability represents a form of homeostasis and is exhibited at multiple stages in the flow of information from the genome to the expression and modification of protein products. Information on the nature of the homeostatic phenomenon at some of these stages is still limited and emerging. This article outlines the various stages at which such neuronal intrinsic plasticity has been observed and draws particular attention to the role of the translation repressor protein, Pumilio, as an important factor in the process. The study of this protein is providing insights into the regulation of neuronal excitability and offers an important research target with benefits to investigators in many areas of neuroscience.     

Structure,Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

Voltage-gated ion channels are crucial for both neuronal and cardiac excitability. Decades of research have begun to unravel the intriguing machinery behind voltage sensitivity. Although the details regarding the arrangement and movement in the voltage-sensor domain are still debated, consensus is slowly emerging. There are three competing conceptual models: the helical-screw, the transporter, and the paddle model. In this review we explore the structure of the activated voltage-sensor domain based on the recent X-ray structure of a chimera between Kv1.2 and Kv2.1. We also present a model for the closed state. From this we conclude that upon depolarization the voltage sensor S4 moves approximately 13 A outwards and rotates approximately 180 degrees, thus consistent with the helical-screw model. S4 also moves relative to S3b which is not consistent with the paddle model. One interesting feature of the voltage sensor is that it partially faces the lipid bilayer and therefore can interact both with the membrane itself and with physiological and pharmacological molecules reaching the channel from the membrane. This type of channel modulation is discussed together with other mechanisms for how voltage-sensitivity is modified. Small effects on voltage-sensitivity can have profound effects on excitability. Therefore, medical drugs designed to alter the voltage dependence offer an interesting way to regulate excitability.     

Calcium/calmodulin-dependent protein kinase II (CaMKII) inhibition induces neurotoxicity via dysregulation of glutamate/calcium signaling and hyperexcitability

Aberrant glutamate and calcium signalings are neurotoxic to specific neuronal populations. Calcium/calmodulin-dependent kinase II (CaMKII), a multifunctional serine/threonine protein kinase in neurons, is believed to regulate neurotransmission and synaptic plasticity in response to calcium signaling produced by neuronal activity. Importantly, several CaMKII substrates control neuronal structure, excitability, and plasticity. Here, we demonstrate that CaMKII inhibition for >4 h using small molecule and peptide inhibitors induces apoptosis in cultured cortical neurons. The neuronal death produced by prolonged CaMKII inhibition is associated with an increase in TUNEL staining and caspase-3 cleavage and is blocked with the translation inhibitor cycloheximide. Thus, this neurotoxicity is consistent with apoptotic mechanisms, a conclusion that is further supported by dysregulated calcium signaling with CaMKII inhibition. CaMKII inhibitory peptides also enhance the number of action potentials generated by a ramp depolarization, suggesting increased neuronal excitability with a loss of CaMKII activity. Extracellular glutamate concentrations are augmented with prolonged inhibition of CaMKII. Enzymatic buffering of extracellular glutamate and antagonism of the NMDA subtype of glutamate receptors prevent the calcium dysregulation and neurotoxicity associated with prolonged CaMKII inhibition. However, in the absence of CaMKII inhibition, elevated glutamate levels do not induce neurotoxicity, suggesting that a combination of CaMKII inhibition and elevated extracellular glutamate levels results in neuronal death. In sum, the loss of CaMKII observed with multiple pathological states in the central nervous system, including epilepsy, brain trauma, and ischemia, likely exacerbates programmed cell death by sensitizing vulnerable neuronal populations to excitotoxic glutamate signaling and inducing an excitotoxic insult itself.     

Ischemia deteriorates the spike encoding of rat cerebellar Purkinje cells by raising intracellular Ca2+

Ischemia-induced excitotoxicity at cerebellar Purkinje cells is presumably due to a persistent glutamate action. To the fact that they are more vulnerable to ischemia than other glutamate-innervated neurons, we studied whether additional mechanisms are present and whether cytoplasm Ca²⁺ plays a key role in their ischemic excitotoxicity. Ischemic changes in the excitability of Purkinje cells were measured by whole-cell recording in cerebellar slices of rats with less glutamate action. The role of cytoplasm Ca²⁺ was examined by two-photon cellular imaging and BAPTA infusion in Purkinje cells. Lowering perfusion rate to cerebellar slices deteriorated spike timing and raised spike capacity of Purkinje cells. These changes were associated with the reduction of spike refractory periods and threshold potentials, as well as the loss of their control to spike encoding. Ischemia-induced functional deterioration at Purkinje neurons was accompanied by cytoplasm Ca²⁺ rise and prevented by BAPTA infusion. Therefore, the ischemia destabilizes the spike encoding of Purkinje cells via raising cytoplasm Ca²⁺ without a need for glutamate, which subsequently causes their excitotoxic death.     

Investigation of the relation between structure and function in myelinated nerve fibres with the aid of ultraviolet radiation

Ultraviolet radiation induces two photochemical alterations relevant to excitability in the nodal membranes: A selective blocking of the sodium permeability and a potential translation of the voltage dependent kinetic parameters of sodium inactivation and activation along the potential axis in the negative direction. The underlying processes are two different photoreactions, since 1) the action spectrum of the blocking effect shows a marked peak near 280 nm and rapidly decreasing sensitivity towards higher and lower wavelengths, while the action spectrum of the potential shift increases with lower wavelengths; 2) the blocking effect is enhanced by a more positive holding potential, while the potential shift is decreased; 3) the potential shift can be prevented intraaxonal application of l-cysteine or 2-mercaptoethanol, but the blocking effect is not affected.Paper presented at the Biomembrane Symposium of the Deutsche Gesellschaft für Biophysik, Freiburg, April 1975.     

Transition between two excitabilities in mesencephalic V neurons

Neurons can make different responses to identical inputs. According to the emerging frequency of repetitive firing, neurons are classified into two types: type 1 and type 2 excitability. Though in mathematical simulations, minor modifications of parameters describing ionic currents can result in transitions between these two excitabilities, empirical evidence to support these theoretical possibilities is scarce. Here we report a joint theoretical and experimental study to test the hypothesis that changes in parameters describing ionic currents cause predictable transitions between the two excitabilities in mesencephalic V (Mes V) neurons. We developed a simple mathematical model of Mes V neurons. Using bifurcation analysis and model simulation, we then predicted that changes in conductance of two low-threshold currents would result in transitions between type 1 and type 2. Finally, by applying specific channel blockers, we observed the transition between two excitabilities forecast by the mathematical model.