Calcium-Dependent Increases in Protein Kinase-A Activity in Mouse Retinal Ganglion Cells Are Mediated by Multiple Adenylate Cyclases

Neurons undergo long term, activity dependent changes that are mediated by activation of second messenger cascades. In particular, calcium-dependent activation of the cyclic-AMP/Protein kinase A signaling cascade has been implicated in several developmental processes including cell survival, axonal outgrowth, and axonal refinement. The biochemical link between calcium influx and the activation of the cAMP/PKA pathway is primarily mediated through adenylate cyclases. Here, dual imaging of intracellular calcium concentration and PKA activity was used to assay the role of different classes of calcium-dependent adenylate cyclases (ACs) in the activation of the cAMP/PKA pathway in retinal ganglion cells (RGCs). Surprisingly, depolarization-induced calcium-dependent PKA transients persist in barrelless mice lacking AC1, the predominant calcium-dependent adenylate cyclase in RGCs, as well as in double knockout mice lacking both AC1 and AC8. Furthermore, in a subset of RGCs, depolarization-induced PKA transients persist during the inhibition of all transmembrane adenylate cyclases. These results are consistent with the existence of a soluble adenylate cyclase that plays a role in calcium-dependent activation of the cAMP/PKA cascade in neurons.     

Synchronization of neuronal assemblies in reciprocally connected cortical areas

Summary To investigate scene segmentation in the visual system we present a model of two reciprocally connected visual areas comprising spiking neurons. The peripheral area P is modeled similar to the primary visual cortex, while the central area C is modeled as an associative memory representing stimulus objects according to Hebbian learning. Without feedback from area C, spikes corresponding to stimulus representations in P are synchronized only locally (slow state). Feedback from C can induce fast oscillations and an increase of synchronization ranges (fast state). Presenting a superposition of several stimulus objects, scene segmentation happens on a time scale of hundreds of milliseconds by alternating epochs of the slow and fast state, where neurons representing the same object are simultaneously in the fast state. We relate our simulation results to various phenomena observed in neurophysiological experiments, such as stimulus-dependent synchronization of fast oscillations, synchronization on different time scales, ongoing activity, and attention-dependent neural activity.     

Regulation of nuclear Ca2+ signaling by translocation of the Ca2+ messenger synthesizing enzyme ADP-ribosyl cyclase during neuronal depolarization

In neurons, voltage-gated Ca(2+) channels and nuclear Ca(2+) signaling play important roles, such as in the regulation of gene expression. However, the link between electrical activity and biochemical cascade activation involved in the generation of the nuclear Ca(2+) signaling is poorly understood. Here we show that depolarization of Aplysia neurons induces the translocation of ADP-ribosyl cyclase, a Ca(2+) messenger synthesizing enzyme, from the cytosol into the nucleus. The translocation is dependent on Ca(2+) influx mainly through the voltage-dependent L-type Ca(2+) channels. We report also that specific nucleoplasmic Ca(2+) signals can be induced by three different calcium messengers, cyclic ADP-ribose, nicotinic acid adenine dinucleotide phosphate (NAADP), both produced by the ADP-ribosyl cyclase, and inositol 1,4,5-trisphosphate (IP(3)). Moreover, our pharmacological data show that NAADP acts on its own receptor, which cooperates with the IP(3) and the ryanodine receptors to generate nucleoplasmic Ca(2+) oscillations. We propose a new model where voltage-dependent L-type Ca(2+) channel-induced nuclear translocation of the cytosolic cyclase is a crucial step in the fine tuning of nuclear Ca(2+) signals in neurons.     

Model of oscillatory activity in thalamic neurons: Role of voltage- and calcium-dependent ionic conductances

This paper describes a computer modeling study of the generation of 10 Hz oscillations in the electrical activity of guinea pig thalamic neurons in vitro. The computer model was based on experimental evidence suggesting that single thalamic neurons in guinea pig have a set of voltage- and calcium-dependent ionic conductances that is capable of generating self-sustained rhythmic oscillations. Simulation results are consistent with this hypothesis, and indicate that a model that contains dendritic calcium and calcium-dependent potassium conductances, as well as a voltage-dependent, slow sodium conductance, can indeed generate self-sustained oscillations like those seen in thalamic neurons. Moreover, simulations indicate that the occurrence of such oscillatory activity is strongly dependent on the location of the slow sodium conductance. Results predict that this slow sodium conductance is located in the dendrites.The authors express their appreciation to R. J. MacGregor for providing equations and computer programs for simulating a two-point neuronal model with active calcium-related conductances     

Electrical and dye coupling in an identified group of neurons in a coelenterate

A compressed network of "giant" neurons, lying within the inner nerve-ring of the hydrozoan jellyfish Polyorchis, functions as the overall pattern generator and the motor neuron system for the subumbrellar swimming musculature. The neurons that form the network are all electrically coupled. The coupling is tight, so that action potentials and slow membrane-potential oscillations are synchronous throughout the network. The fluorescent dye Lucifer Yellow CH passes throughout the network following iontophoretic injection into a single neuron. The sites of both current and dye passage are presumably the numerous gap junctions which are found where the giants run together. Based on the morphological identification of the giant network from the dye injections and ultrastructural studies, the electrophysiological data on the firing pattern and input--output relations of the network, and its position relative to other neurons in the inner nerve-ring, the giant network can be considered an identified neuronal group.     

Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors

Fast excitatory neurotransmission is mediated by activation of synaptic ionotropic glutamate receptors. In hippocampal slices, we report that stimulation of Schaffer collaterals evokes in CA1 neurons delayed inward currents with slow kinetics, in addition to fast excitatory postsynaptic currents. Similar slow events also occur spontaneously, can still be observed when neuronal activity and synaptic glutamate release are blocked, and are found to be mediated by glutamate released from astrocytes acting preferentially on extrasynaptic NMDA receptors. The slow currents can be triggered by stimuli that evoke Ca2+ oscillations in astrocytes, including photolysis of caged Ca2+ in single astrocytes. As revealed by paired recording and Ca2+ imaging, a striking feature of this NMDA receptor response is that it occurs synchronously in multiple CA1 neurons. Our results reveal a distinct mechanism for neuronal excitation and synchrony and highlight a functional link between astrocytic glutamate and extrasynaptic NMDA receptors.     

A model of oscillation generation by molluscan neurons

A model describing slow oscillations of membrane potential in molluscan neurons is suggested. It is based on the view that the depolarization phase is due to the slow calcium current, whereas the hyperpolarization phase is due to the potassium current activated by intracellular Ca ions. It is shown that depending on values of the parameters of the model there are three possible types of electrical activity of the neurons: stable membrane hyperpolarization up to the resting potential which is between ?49 and ?53 mV; slow oscillations of membrane potential from ?30 to ?60 mV, with a period of 12–17 sec, and stable membrane depolarization to between ?40 and ?30 mV, which may lead to the onset of stable rhythmic activity of these neurons. Dependence of the amplitude of the oscillations of potential on the extracellular concentration of Ca, K, and Na ions was calculated and agrees qualitatively with the experimental data of Barker and Gainer [4].     

Role of voltage-dependent modulation of store Ca2+ release in synchronization of Ca2+ oscillations

Slow waves are rhythmic depolarizations that underlie mechanical activity of many smooth muscles. Slow waves result through rhythmic Ca(2+) release from intracellular Ca(2+) stores through inositol 1,4,5-trisphosphate (IP(3)) sensitive receptors and Ca(2+)-induced Ca(2+) release. Ca(2+) oscillations are transformed into membrane depolarizations by generation of a Ca(2+)-activated inward current. Importantly, the store Ca(2+) oscillations that underlie slow waves are entrained across many cells over large distances. It has been shown that IP(3) receptor-mediated Ca(2+) release is enhanced by membrane depolarization. Previous studies have implicated diffusion of Ca(2+) or the second messenger IP(3) across gap junctions in synchronization of Ca(2+) oscillations. In this study, a novel mechanism of Ca(2+) store entrainment through depolarization-induced IP(3) receptor-mediated Ca(2+) release is investigated. This mechanism is significantly different from chemical coupling-based mechanisms, as membrane potential has a coupling effect over distances several orders of magnitude greater than either diffusion of Ca(2+) or IP(3) through gap junctions. It is shown that electrical coupling acting through voltage-dependent modulation of store Ca(2+) release is able to synchronize oscillations of cells even when cells are widely separated and have different intrinsic frequencies of oscillation.     

Active hippocampal networks undergo spontaneous synaptic modification

The brain is self-writable; as the brain voluntarily adapts itself to a changing environment, the neural circuitry rearranges its functional connectivity by referring to its own activity. How the internal activity modifies synaptic weights is largely unknown, however. Here we report that spontaneous activity causes complex reorganization of synaptic connectivity without any external (or artificial) stimuli. Under physiologically relevant ionic conditions, CA3 pyramidal cells in hippocampal slices displayed spontaneous spikes with bistable slow oscillations of membrane potential, alternating between the so-called UP and DOWN states. The generation of slow oscillations did not require fast synaptic transmission, but their patterns were coordinated by local circuit activity. In the course of generating spontaneous activity, individual neurons acquired bidirectional long-lasting synaptic modification. The spontaneous synaptic plasticity depended on a rise in intracellular calcium concentrations of postsynaptic cells, but not on NMDA receptor activity. The direction and amount of the plasticity varied depending on slow oscillation patterns and synapse locations, and thus, they were diverse in a network. Once this global synaptic refinement occurred, the same neurons now displayed different patterns of spontaneous activity, which in turn exhibited different levels of synaptic plasticity. Thus, active networks continuously update their internal states through ongoing synaptic plasticity. With computational simulations, we suggest that with this slow oscillation-induced plasticity, a recurrent network converges on a more specific state, compared to that with spike timing-dependent plasticity alone.     

Inhibition of Nitric Oxide Synthase Blocks N-Methyl-D-Aspartate-, Quisqualate-, Kainate-, Harmaline-, and Pentylenetetrazole-Dependent Increases in Cerebellar Cyclic GMP In Vivo

The synthesis of nitric oxide by brain slices has been demonstrated in several laboratories. In addition, in vitro studies have demonstrated stimulation of nitric oxide synthesis by excitatory amino acid receptor agonists. These data have led to the hypothesis that this readily diffusible "intercellular messenger molecule" acts to generate a cascade effect by activating guanylate cyclase in several cell types and thereby augment levels of the second messenger cyclic GMP (cGMP). Therefore, we evaluated this hypothesis in vivo, by testing the actions of the nitric oxide synthase inhibitor N-mono-methyl-L-arginine (NMMA) on elevations in level of mouse cerebellar cGMP generated by excitatory amino acid receptor agonists. The stimulatory effects of D-serine, quisqualate, and kainate were all found to be antagonized by this enzyme inhibitor. In addition, NMMA antagonized the increases in cerebellar cGMP level elicited by harmaline and pentylenetetrazole, pharmacological agents that augment endogenous excitatory amino acid transmission. Our data are, therefore, the first in vivo demonstration that nitric oxide is an important "messenger molecule" in the cerebellum, mediating the actions of kainate, quisqualate, and N-methyl-D-aspartate receptor agonists on guanylate cyclase. These data are consistent with previous in vitro findings with kainate and N-methyl-D-aspartate.     

Electrical signals in olfactory transduction.

Olfactory transduction involves a G-protein-coupled second messenger system, which results in the odor-dependent production of cAMP. The direct activation of ion channels in the cilia membrane by cAMP is the final step in producing the slow depolarization that brings the membrane potential to threshold for spike generation. Because of the central role in the transduction cascade occupied by these channels considerable effort has been directed toward understanding their behavior at a molecular level. Alternative second messenger pathways have also been proposed in olfaction, but the physiological evidence for these is less well developed.     

Oscillations and slow patterning in the antennal lobe

Odor presentation generates both fast oscillations and slow patterning in the spiking activity of the projection neurons (PNs) in the antennal lobe (AL) of locusts, moths and bees. Experimental results indicate that the oscillations are the result of the interaction between the PNs and the inhibitory local neurons (LNs) in the AL; e.g., blocking inhibition by application of GABA-receptor antagonists abolishes these oscillations. The slow patterning, on the other hand, was shown to be somewhat resistant to such blockage. In a H-H model, we reproduce both the oscillations and the slow patterning. As previously suggested, the oscillations are the result of the interaction between the PNs and LNs. We suggest that calcium and calcium-dependent potassium channels (found in PNs of bees and moths) are sufficient to account for the slow patterning resistant to the application of GABA-receptor antagonists. The intrinsic bursting property of the PNs, resulting from these additional modeled currents, give rise to another network feature that was seen experimentally in locusts: A relatively small increase in the number of additional generated PN action potentials when LN input is blocked. Consequently, the major effect of network inhibition is to redistribute the action potentials of the PNs from bursting to one action potential per cycle of the oscillations. Action Editor: Christiane Linster     

Kinetic models of odor transduction implemented as artificial neural networks

We present a formal model of olfactory transduction corresponding to the biochemical reaction cascade found in chemosensory neurons. It assumes that odorants bind to receptor proteins which, in turn, activate transducer mechanisms corresponding to second messenger-mediated processes. The model is reformulated as a mathematically equivalent artificial neural network (ANN). To enable comparison of the computational power of our model, previously suggested models of chemosensory transduction are also presented in ANN versions. In ANNs, certain biological parameters, such as rate constants and affinities, are transformed into weights that can be fitted by training with a given experimental data set. After training, these weights do not necessarily equal the real biological parameters, but represent a set of values that is sufficient to simulate an experimental set of data. We used ANNs to simulate data recorded from bee subplacodes and compare the capacity of our model with ANN versions of other models. Receptor neurons of the nonpheromonal, general odor-processing subsystem of the honeybee are broadly tuned, have overlapping response spectra, and show highly nonlinear concentration dependencies and mixture interactions, i.e., synergistic and inhibitory effects. Our full model alone has the necessary complexity to simulate these complex response characteristics. To account for the complex response characteristics of honeybee receptor neurons, we suggest that several different receptor protein types and at least two second messenger systems are necessary that may interact at various levels of the transduction cascade and may eventually have opposing effects on receptor neuron excitability.     

The influence of sodium and potassium dynamics on excitability,seizures, and the stability of persistent states: II. Network and glial dynamics

In these companion papers, we study how the interrelated dynamics of sodium and potassium affect the excitability of neurons, the occurrence of seizures, and the stability of persistent states of activity. We seek to study these dynamics with respect to the following compartments: neurons, glia, and extracellular space. We are particularly interested in the slower time-scale dynamics that determine overall excitability, and set the stage for transient episodes of persistent oscillations, working memory, or seizures. In this second of two companion papers, we present an ionic current network model composed of populations of Hodgkin–Huxley type excitatory and inhibitory neurons embedded within extracellular space and glia, in order to investigate the role of micro-environmental ionic dynamics on the stability of persistent activity. We show that these networks reproduce seizure-like activity if glial cells fail to maintain the proper micro-environmental conditions surrounding neurons, and produce several experimentally testable predictions. Our work suggests that the stability of persistent states to perturbation is set by glial activity, and that how the response to such perturbations decays or grows may be a critical factor in a variety of disparate transient phenomena such as working memory, burst firing in neonatal brain or spinal cord, up states, seizures, and cortical oscillations.

Dynamic Interaction of Spindles and Gamma Activity during Cortical Slow Oscillations and Its Modulation by Subcortical Afferents

Slow oscillations are a hallmark of slow wave sleep. They provide a temporal framework for a variety of phasic events to occur and interact during sleep, including the expression of high-frequency oscillations and the discharge of neurons across the entire brain. Evidence shows that the emergence of distinct high-frequency oscillations during slow oscillations facilitates the communication among brain regions whose activity was correlated during the preceding waking period. While the frequencies of oscillations involved in such interactions have been identified, their dynamics and the correlations between them require further investigation. Here we analyzed the structure and dynamics of these signals in anesthetized rats. We show that spindles and gamma oscillations coexist but have distinct temporal dynamics across the slow oscillation cycle. Furthermore, we observed that spindles and gamma are functionally coupled to the slow oscillations and between each other. Following the activation of ascending pathways from the brainstem by means of a carbachol injection in the pedunculopontine nucleus, we were able to modify the gain in the gamma oscillations that are independent of the spindles while the spindle amplitude was reduced. Furthermore, carbachol produced a decoupling of the gamma oscillations that are dependent on the spindles but with no effect on their amplitude. None of the changes in the high-frequency oscillations affected the onset or shape of the slow oscillations, suggesting that slow oscillations occur independently of the phasic events that coexist with them. Our results provide novel insights into the regulation, dynamics and homeostasis of cortical slow oscillations.     

Sleepy dialogues between cortex and hippocampus: who talks to whom?

During NREM sleep, neocortical neurons undergo near-synchronous transitions, every second or so, between UP states, during which they are depolarized and fire actively, and DOWN states, during which they are hyperpolarized and completely silent. In this issue of Neuron, Isomura et al. report that slow oscillations of membrane potential occur near-synchronously not only in neocortex but also in entorhinal cortex and subiculum. Within the hippocampus proper, pyramidal neurons lack the bistability of UP and DOWN states, but their firing is strongly modulated by cortical activity during the UP state. Intriguingly, many hippocampal neurons fire during the cortical DOWN state. Thus, during sleep UP states, the cortex can talk to the hippocampus, but it is unclear whether the hippocampus talks back.     

Thalamocortical dynamics of sleep: roles of purinergic neuromodulation

Thalamocortical dynamics, the millisecond to second changes in activity of thalamocortical circuits, are central to perception, action and cognition. Generated by local circuitry and sculpted by neuromodulatory systems, these dynamics reflect the expression of vigilance states. In sleep, thalamocortical dynamics are thought to mediate "offline" functions including memory consolidation and synaptic scaling. Here, I discuss thalamocortical sleep dynamics and their modulation by the ascending arousal system and locally released neurochemicals. I focus on modulation of these dynamics by electrically silent astrocytes, highlighting the role of purinergic signaling in this glial form of communication. Astrocytes modulate cortical slow oscillations, sleep behavior, and sleep-dependent cognitive function. The discovery that astrocytes can modulate sleep dynamics and sleep-related behaviors suggests a new way of thinking about the brain, in which integrated circuits of neurons and glia control information processing and behavioral output.     

Selective coupling between theta phase and neocortical fast gamma oscillations during REM-sleep in mice

Background

The mammalian brain expresses a wide range of state-dependent network oscillations which vary in frequency and spatial extension. Such rhythms can entrain multiple neurons into coherent patterns of activity, consistent with a role in behaviour, cognition and memory formation. Recent evidence suggests that locally generated fast network oscillations can be systematically aligned to long-range slow oscillations. It is likely that such cross-frequency coupling supports specific tasks including behavioural choice and working memory.

Principal Findings

We analyzed temporal coupling between high-frequency oscillations and EEG theta activity (4–12 Hz) in recordings from mouse parietal neocortex. Theta was exclusively present during active wakefulness and REM-sleep. Fast oscillations occurred in two separate frequency bands: gamma (40–100 Hz) and fast gamma (120–160 Hz). Theta, gamma and fast gamma were more prominent during active wakefulness as compared to REM-sleep. Coupling between theta and the two types of fast oscillations, however, was more pronounced during REM-sleep. This state-dependent cross-frequency coupling was particularly strong for theta-fast gamma interaction which increased 9-fold during REM as compared to active wakefulness. Theta-gamma coupling increased only by 1.5-fold.

Significance

State-dependent cross-frequency-coupling provides a new functional characteristic of REM-sleep and establishes a unique property of neocortical fast gamma oscillations. Interactions between defined patterns of slow and fast network oscillations may serve selective functions in sleep-dependent information processing.