Intrinsic Cellular Properties Research Articles

Astrocytes process synaptic information

Astrocytes were classically considered as simple supportive cells for neurons without a significant role in information processing by the nervous system. However, considerable amounts of evidence obtained by several groups during the past years demonstrated the existence of a bidirectional communication between astrocytes and neurons, which prompted a re-examination of the role of astrocytes in the physiology of the nervous system. While neurons base their excitability on electrical signals generated across the membrane, astrocytes base their cellular excitability on variations of the Ca2+ concentration in the cytosol. This article discusses our current knowledge of the properties of the synaptically evoked astrocyte Ca2+ signal, which reveals that astrocytes display integrative properties for synaptic information processing. Astrocytes respond selectively to different axon pathways, discriminate between the activity of different synapses and their Ca2+ signal is non-linearly modulated by the simultaneous activity of different synaptic inputs. Furthermore, this Ca2+ signal modulation depends on astrocyte cellular intrinsic properties and is bidirectionally regulated by the level of synaptic activity. Finally, astrocyte Ca2+ elevations can trigger the release of gliotransmitters, which modulate neuronal activity as well as synaptic transmission and plasticity, hence granting the bidirectional communication with neurons. Consequently, astrocytes can be considered as cellular elements involved in information processing by the nervous system.

Calcium sensor properties for activity-dependent homeostatic regulation of pyloric network rhythms in the lobster stomatogastric ganglion

Event Abstract Back to Event Calcium sensor properties for activity-dependent homeostatic regulation of pyloric network rhythms in the lobster stomatogastric ganglion Cengiz Günay1*, R.M Hooper1, K.R Hammett1 and A.A Prinz1 1 University of Zagreb, United States Homeostatic regulation has been proposed as a mechanism that can explain the robust behavior of central pattern generating (CPG) neural networks observed experimentally. CPG networks, such as the pyloric network in the stomatogastric ganglion (STG) of the lobster, generate stable patterns of activity in spite of constant molecular turnover and environmental changes. Although the sensing and acting components of regulation are not yet well understood, one likely scenario is that calcium-based activity sensors drive the regulation of intrinsic cellular and synaptic properties. It has been shown that calcium can help maintain stable activity levels in individual model neurons [1], and pyloric rhythms in one network model [2]. Remaining questions are: (1) whether calcium sensors work in different network model versions, and (2) what intrinsic properties of calcium sensors are important for distinguishing functional from non-functional activity patterns. We tested an existing database of about 20 million simplified pyloric networks, constructed by varying the three lateral pyloric (LP), pyloric (PY) and anterior burster and pyloric dilator (AB/PD) neuron models and their synaptic strengths [3], to see if calcium sensors can distinguish functional pyloric activity. A set of three sensors---a fast (F), slow (S) and DC (D) sensor---in each neuron, could classify 88% of the networks correctly as functional or non-functional. To find properties necessary for these sensors, we constructed a set of 354 sensors with different activation and inactivation rates and sensitivities to calcium. We determined that there were optimal values for sensor parameters, but they were broadly tuned around these values and were independent from each other. Taken together, our results suggest that activity sensing for homeostatic regulation of the pyloric network can potentially be achieved with relatively few, simple calcium sensors and that the properties of these sensors need not necessarily be adjusted to the particular role of each neuron in the network. This work is supported by 1 R01 NS054911-01A1 from NINDS.Liu Z, Golowasch J, Marder E and Abbott LF. J. Neurosci.1998, 18(7):2309-2320

Artificial synaptic modification reveals a dynamical invariant in the pyloric CPG

The sequential firing of neurons in central pattern generators (CPGs) is generally thought to be a result of an interaction between intrinsic cellular and synaptic properties of the component neurons. Due to experimental limitations, it is usually difficult to address the role of each of these properties separately. We have done so by using the crustacean stomatogastric CPG and the dynamic clamp technique to measure how the network responds to the selective modification of an individual important synapse. Our results show that the burst periods and the phase lags between the constrictor (LP) and dilator (PD) neurons across preparations showed significant variability during equivalent experimental manipulations. Despite this variability, the ratio between the change in the burst period and the change in the phase lag between the same neurons was tightly preserved in all preparations, revealing a dynamical invariant in the system. This dynamical invariant was preserved despite the individual variability in the period and phase lag measurements, suggesting a tightly regulated constraint between the parameters of the network.

Modeling large-scale neural network culture interface on very-high density multi-electrode arrays

The use of multi-electrode arrays (MEA) technology is developing in neuroscience fields like neuro-pharmacology [1,2], network plasticity investigation [3-5] or neurological diseases [6] and disorders [7]. Dissociated cultures or slices are now often employed on 60–100 multi-site arrays. Recently, matrixes of several thousands of microelectrodes have been developed in order to gain higher spatial resolution from the cell scale up to large network scale. With the framework of a European Consortium (IDEA Project) we developed a 4096 electrode MEA using the Active Pixel Sensor APS technology as well as a computer model of cortical dissociated cultures grown on this device including the neuron-to-electrode interface. Our goal is to better understand the network mechanisms responsible for recorded activity, and to provide integrated software for Computer Aided Design (CAD) of neural engineering devices. Since it was computationally too heavy to work with thousands of interconnected Hodgkin-Huxley cell models, we chose to implement the Izhikevich model which is known as a good compromise between realistic cellular properties and computation time [8]. Indeed, the classical standard leaky integrate-and-fire cellular model can hardly mimic the rich repertoire of intrinsic cellular properties that can be found in biological substrates. We present here the first recordings of high-density MEAs together with dedicated software which can simulate the complete system composed of the electrode matrix and the biological network grown on top. The first results of these large-scale interconnected networks simulations (size and number of cells similar to those recorded in vitro) are consistent with the first recorded data using our prototype of high-density MEAs: (i) the bursts initiation location varies randomly from one place to another, (ii) their propagation varies with the connectivity and the level of presynaptic firing, (iii) the average bursting frequency with no inhibitory connections is close to 1 Hz and similar activity is obtained with bicucculin treated dissociated culture activity. Finally, (iv) the model burst propagation speed is about 100 mm/s and this value has also been computed on real cultures in our lab. This tool is currently used to optimize the design and to investigate the properties of large-scale MEA devices under development and constitutes an innovative neuro-engineering CAD environment.

Integrated Mechanisms of Anticipation and Rate-of-Change Computations in Cortical Circuits

Local neocortical circuits are characterized by stereotypical physiological and structural features that subserve generic computational operations. These basic computations of the cortical microcircuit emerge through the interplay of neuronal connectivity, cellular intrinsic properties, and synaptic plasticity dynamics. How these interacting mechanisms generate specific computational operations in the cortical circuit remains largely unknown. Here, we identify the neurophysiological basis of both the rate of change and anticipation computations on synaptic inputs in a cortical circuit. Through biophysically realistic computer simulations and neuronal recordings, we show that the rate-of-change computation is operated robustly in cortical networks through the combination of two ubiquitous brain mechanisms: short-term synaptic depression and spike-frequency adaptation. We then show how this rate-of-change circuit can be embedded in a convergently connected network to anticipate temporally incoming synaptic inputs, in quantitative agreement with experimental findings on anticipatory responses to moving stimuli in the primary visual cortex. Given the robustness of the mechanism and the widespread nature of the physiological machinery involved, we suggest that rate-of-change computation and temporal anticipation are principal, hard-wired functions of neural information processing in the cortical microcircuit.

Intrinsic electrical properties of spinal motoneurons vary with joint angle

The dendrites of spinal motoneurons amplify synaptic inputs to a marked degree through persistent inward currents (PICs). Dendritic amplification is subject to neuromodulatory control from the brainstem by axons releasing the monoamines serotonin and norepinephrine; however, the monoaminergic projection to the cord is diffusely organized and does not allow independent adjustment of amplification in different motor pools. Using in vivo voltage-clamp techniques, here we show that dendritic PICs in ankle extensor motoneurons in the cat are reduced about 50% by small rotations (+/-10 degrees ) of the ankle joint. This reduction is primarily due to reciprocal inhibition, a tightly focused input shared only among strict muscle antagonists. These results demonstrate how a specific change in limb position can regulate intrinsic cellular properties set by a background of diffuse descending neuromodulation.

Normal electrical properties of hippocampal neurons modelling early Huntington disease pathogenesis

Huntington disease (HD) is a neurodegenerative disorder caused by an unstable and progressive expansion of a CAG trinucleotide repeat tract in the HD gene. Previous studies using truncated forms of the HD gene have shown pronounced deficits in synaptic transmission and plasticity but rather modest changes in intrinsic cellular properties, despite overt pathology. The knock-in mice carrying a 72–80 CAG repeat mutation is an accurate genetic model of early stage HD, displaying a more subtle disease phenotype. To relate full-length HD gene expression and differential polyglutamine expansion with possible pathophysiological changes in salient electrophysiological properties of neurons that may underlie early symptoms of HD, including mood and cognitive impairments, we have conducted whole-cell recordings from hippocampal area CA1 pyramidal cells in Hdh6/Q72 and Hdh4/Q80 knock-in mice. Electrophysiological characterisation of cells obtained from young adult (< 4 months) HD mice harbouring an expanded CAG repeat stretch and age-matched wild type (WT) mice revealed no significant differences in any of the active or passive membrane properties investigated. Similar findings, showing a lack of significant differences in cellular electrical properties, were obtained from cells of aged (> 18 months) HD mice and WT controls, despite modest levels of repeat length variability demonstrated by single cell PCR. Thus, the current study indicates a lack of overt changes in the electrical membrane properties of pyramidal cells in HD mice accurately modelling early stage HD pathology. Furthermore, together with our previous work, these findings point to a synaptic rather than cellular locus of HD-related pathology.

Sequential structure of neocortical spontaneous activity in vivo

Even in the absence of sensory stimulation, the neocortex shows complex spontaneous activity patterns, often consisting of alternating "DOWN" states of generalized neural silence and "UP" states of massive, persistent network activity. To investigate how this spontaneous activity propagates through neuronal assemblies in vivo, we simultaneously recorded populations of 50-200 cortical neurons in layer V of anesthetized and awake rats. Each neuron displayed a virtually unique spike pattern during UP states, with diversity seen amongst both putative pyramidal cells and interneurons, reflecting a complex but stereotypically organized sequential spread of activation through local cortical networks. Spike timing was most precise during the first approximately 100 ms after UP state onset, and decayed as UP states progressed. A subset of UP states propagated as traveling waves, but waves passing a given point in either direction initiated similar local sequences, suggesting local networks as the substrate of sequential firing patterns. A search for repeating motifs indicated that their occurrence and structure was predictable from neurons' individual latencies to UP state onset. We suggest that these stereotyped patterns arise from the interplay of intrinsic cellular conductances and local circuit properties.

The contribution of the pleural type 12 interneuron to swim acceleration in Clione limacina

The pteropod mollusc, Clione limacina, swims by alternate dorsal-ventral flapping movements of its wing-like parapodia. The basic swim rhythm is produced by a network of pedal swim interneurons that comprise a swim central pattern generator (CPG). Serotonergic modulation of both intrinsic cellular properties of the swim interneurons and network properties contribute to swim acceleration, the latter including recruitment of type 12 interneurons into the CPG. Here we address the role of the type 12 interneurons in swim acceleration. A single type 12 interneuron is found in each of the pleural ganglia, which contributes to fast swimming by exciting the dorsal swim interneurons while simultaneously inhibiting the ventral swim interneurons. Each type 12 interneuron sends a single process through the pleural-pedal connective that branches in both ipsilateral and contralateral pedal ganglia. This anatomical arrangement allowed us to manipulate the influence of the type 12 interneurons on the swim circuitry by cutting the pleural-pedal connective followed by a "culture" period of 48 h. The mean swim frequency of cut preparations was reduced by 19% when compared to the swim frequency of uncut preparations when stimulated with 10(-6) M serotonin; however, this decrease was not statistically significant. Additional evidence suggests that the type 12 interneurons may produce a short-term, immediate effect on swim acceleration while slower, modulatory inputs are taking shape.

The Synaptic Mechanism of Direction Selectivity in Distal Processes of Starburst Amacrine Cells

Patch-clamp recordings revealed that distal processes of starburst amacrine cells (SACs) received largely excitatory synaptic input from the receptive field center and nearly purely inhibitory inputs from the surround during both stationary and moving light stimulations. The direct surround inhibition was mediated mainly by reciprocal GABA(A) synapses between opposing SACs, which provided leading and prolonged inhibition during centripetal stimulus motion. Simultaneous Ca(2+) imaging and current-clamp recording during apparent-motion stimulation further demonstrated the contributions of both centrifugal excitation and GABA(A/C)-receptor-mediated centripetal inhibition to the direction-selective Ca(2+) responses in SAC distal processes. Thus, by placing GABA release sites in electrotonically semi-isolated distal processes and endowing these sites with reciprocal GABA(A) synapses, SACs use a radial-symmetric center-surround receptive field structure to build a polar-asymmetric circuitry. This circuitry may integrate at least three levels of interactions--center excitation, surround inhibition, and reciprocal inhibitions that amplify the center--surround antagonism-to generate robust direction selectivity in the distal processes.

Presynaptic Mechanism for Slow Contrast Adaptation in Mammalian Retinal Ganglion Cells

Visual neurons, from retina to cortex, adapt slowly to stimulus contrast. Following a switch from high to low contrast, a neuron rapidly decreases its responsiveness and recovers over 5-20 s. Cortical adaptation arises from an intrinsic cellular mechanism: a sodium-dependent potassium conductance that causes prolonged hyperpolarization. Spiking can drive this mechanism, raising the possibility that the same mechanism exists in retinal ganglion cells. We found that adaptation in ganglion cells corresponds to a slowly recovering afterhyperpolarization (AHP), but, unlike in cortical cells, this AHP is not primarily driven by an intrinsic cellular property: spiking was not sufficient to generate adaptation. Adaptation was strongest following spatial stimuli tuned to presynaptic bipolar cells rather than the ganglion cell; it was driven by a reduced excitatory conductance, and it persisted while blocking GABA and glycine receptors, K((Ca)) channels, or mGluRs. Thus, slow adaptation arises from reduced glutamate release from presynaptic (nonspiking) bipolar cells.

Response Properties of Dural Nociceptors in Relation to Headache

Single-unit electrophysiological recording studies have examined the activity of sensory neurons in the trigeminal ganglion that innervate the intracranial meninges to better understand their possible role in headache. A key question is whether the meningeal sensory neurons are similar to nociceptive neurons in other tissues or, alternatively, whether they have unique properties that might be of significance for headache pathogenesis and drug therapy. Such studies have indeed found that the intracranial dura is innervated by neurons that exhibit properties characteristic of nociceptors in other tissues, including chemosensitivity and sensitization. This sensitization, consisting of an enhanced responsiveness to mechanical stimuli, might be relevant to symptoms that are characteristic of certain headaches that indicate the presence of an exaggerated intracranial mechanosensitivity. Studies that examined whether the anti-migraine agent sumatriptan might inhibit this sensitization (in addition to its well-known inhibition of neurotransmitter release) found that it had no inhibitory effect but rather produced a calcium-dependent discharge, which might account for the initial worsening of headache that can follow sumatriptan administration. In studies that examined the effects of vasodilator agents, nitroprusside produced mixed effects on mechanosensitivity, whereas calciton gene-related peptide (CGRP) had no effect on either spontaneous or mechanically evoked discharge. These results call into question the role of vasodilation in headache and suggest that the role of CGRP in headache may be through its action as a central neurotransmitter rather than through vasodilation and activation of meningeal nociceptors. In general, studies of meningeal sensory neurons have not found evidence of unique properties that distinguish them from nociceptive neurons in other tissues. Ultimately the distinctive clinical characteristics of headache may prove to be related not so much to any differences in the intrinsic molecular or cellular properties of the meningeal sensory neurons but rather to the distinctive properties of the tissue that they innervate.

Synaptic information processing by astrocytes

Glial cells were classically considered as supportive cells that do not contribute to information processing in the nervous system. However, considerable amount of evidence obtained by several groups during the last few years has demonstrated the existence of a bidirectional communication between astrocytes and neurons, which prompted a re-examination of the role of glial cells in the physiology of the nervous system. This review will discuss recent advances in the neuron-to-astrocyte communication, focusing on the recently reported properties of the synaptically evoked astrocyte Ca 2+ signal that indicate that astrocytes show integrative properties for synaptic information processing. Indeed, we have recently shown that hippocampal astrocytes discriminate between the activity of different synapses, and respond selectively to different axon pathways. Furthermore, the astrocyte Ca 2+ signal is modulated by the simultaneous activity of different synaptic inputs. This Ca 2+ signal modulation depends on cellular intrinsic properties of the astrocytes, is bidirectionally regulated by the level of synaptic activity, and controls the spatial extension of the intracellular Ca 2+ signal. Consequently, we propose that astrocytes can be considered as cellular elements involved in information processing by the nervous system.

Glial calcium signaling and neuron–glia communication

The existence of bidirectional signaling between astrocytes and neurons has revealed an important active role of astrocytes in the physiology of the nervous system. As a consequence, there is a new concept of the synaptic physiology—“the tripartite synapse”, where astrocytes exchange information with the pre- and postsynaptic elements and participate as dynamic regulatory elements in neurotransmission. The control of the Ca 2+ excitability in astrocytes is a key element in this loop of information exchange. The ability of astrocytes to respond to neuronal activity and discriminate between the activity of different synapses, the modulation of the astrocytic cellular excitability by the synaptic activity, and the expression of cellular intrinsic properties indicate that astrocytes are endowed with cellular computational characteristics that process synaptic information. Therefore, we propose that astrocytes can be considered as cellular elements involved in the information processing by the nervous system.

Formation of heteromeric hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the hippocampus is regulated by developmental seizures

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate hyperpolarization-activated currents (I(h)). In hippocampus, these currents contribute greatly to intrinsic cellular properties and synchronized neuronal activity. The kinetic and gating properties of HCN-mediated currents are largely determined by the type of subunits--for example, HCN1 and HCN2--that assemble to form homomeric channels. Recently, functional heteromeric HCN channels have been described in vitro, further enlarging the potential I(h) repertoire of individual neurons. Because these heteromeric HCN channels may promote hippocampal hyperexcitability and the development of epilepsy, understanding the mechanisms governing their formation is of major clinical relevance. Here, we find that developmental seizures promote co-assembly of hippocampal HCN1/HCN2 heteromeric channels, in a duration-dependent manner. Long-lasting heteromerization was found selectively after seizures that provoked persistent hippocampal hyperexcitability. The mechanism for this enhanced heteromerization may involve increased relative abundance of HCN2-type subunits relative to the HCN1 isoform at both mRNA and protein levels. These data suggest that heteromeric HCN channels may provide molecular targets for intervention in the epileptogenic process.

Integrated Mechanisms of Anticipation and Rate-of-Change Computations in Cortical Circuits

Local neocortical circuits are characterized by stereotypical physiological and structural features that subserve generic computational operations. These basic computations of the cortical microcircuit emerge through the interplay of neuronal connectivity, cellular intrinsic properties, and synaptic plasticity dynamics. How these interacting mechanisms generate specific computational operations in the cortical circuit remains largely unknown. Here, we identify the neurophysiological basis of both the rate of change and anticipation computations on synaptic inputs in a cortical circuit. Through biophysically realistic computer simulations and neuronal recordings, we show that the rate-of-change computation is operated robustly in cortical networks through the combination of two ubiquitous brain mechanisms: short-term synaptic depression and spike-frequency adaptation. We then show how this rate-of-change circuit can be embedded in a convergently connected network to anticipate temporally incoming synaptic inputs, in quantitative agreement with experimental findings on anticipatory responses to moving stimuli in the primary visual cortex. Given the robustness of the mechanism and the widespread nature of the physiological machinery involved, we suggest that rate-of-change computation and temporal anticipation are principal, hard-wired functions of neural information processing in the cortical microcircuit.

Potent block of Cx36 and Cx50 gap junction channels by mefloquine.

Recently, great interest has been shown in understanding the functional roles of specific gap junction proteins (connexins) in brain, lens, retina, and elsewhere. Some progress has been made by studying knockout mice with targeted connexin deletions. For example, such studies have implicated the gap junction protein Cx36 in synchronizing rhythmic activity of neurons in several brain regions. Although knockout strategies are informative, they can be problematic, because compensatory changes sometimes occur during development. Therefore, it would be extremely useful to have pharmacological agents that block specific connexins, without major effects on other gap junctions or membrane channels. We show that mefloquine, an antimalarial drug, is one such agent. It blocked Cx36 channels, expressed in transfected N2A neuroblastoma cells, at low concentrations (IC(50) approximately 300 nM). Mefloquine also blocked channels formed by the lens gap junction protein, Cx50 (IC(50) approximately 1.1 microM). However, other gap junctions (e.g., Cx43, Cx32, and Cx26) were only affected at concentrations 10- to 100-fold higher. To further examine the utility and specificity of this compound, we characterized its effects in acute brain slices. Mefloquine, at 25 microM, blocked gap junctional coupling between interneurons in neocortical slices, with minimal nonspecific actions. At this concentration, the only major side effect was an increase in spontaneous synaptic activity. Mefloquine (25 microM) caused no significant change in evoked excitatory or inhibitory postsynaptic potentials, and intrinsic cellular properties were also mostly unaffected. Thus, mefloquine is expected to be a useful tool to study the functional roles of Cx36 and Cx50.

Reflections on respiratory rhythm generation

Knowledge about neuronal mechanisms that control respiration is being advanced rapidly by studies that make use of both mature in vivo animals and in vitro neonates. The available data suggest that particular types of neurons within selected networks of the ventrolateral medulla are essential for respiratory rhythm generation. There are many uncertainties, however, about the correspondence between neurons identified by the above two approaches, because there are virtually no studies that have combined them. In this chapter, I propose a hypothesis that shows how neonatal respiratory neurons, with either retained or modified intrinsic cellular properties, develop into mature, well-characterized respiratory neurons located in medullary areas called the Bötzinger and pre-Bötzinger complex. Currently, the most plausible models of respiratory rhythmogenesis are hybrid ones that include both intrinsic cellular and network properties.

Interactions between membrane conductances underlying thalamocortical slow-wave oscillations.

Neurons of the central nervous system display a broad spectrum of intrinsic electrophysiological properties that are absent in the traditional "integrate-and-fire" model. A network of neurons with these properties interacting through synaptic receptors with many time scales can produce complex patterns of activity that cannot be intuitively predicted. Computational methods, tightly linked to experimental data, provide insights into the dynamics of neural networks. We review this approach for the case of bursting neurons of the thalamus, with a focus on thalamic and thalamocortical slow-wave oscillations. At the single-cell level, intrinsic bursting or oscillations can be explained by interactions between calcium- and voltage-dependent channels. At the network level, the genesis of oscillations, their initiation, propagation, termination, and large-scale synchrony can be explained by interactions between neurons with a variety of intrinsic cellular properties through different types of synaptic receptors. These interactions can be altered by neuromodulators, which can dramatically shift the large-scale behavior of the network, and can also be disrupted in many ways, resulting in pathological patterns of activity, such as seizures. We suggest a coherent framework that accounts for a large body of experimental data at the ion-channel, single-cell, and network levels. This framework suggests physiological roles for the highly synchronized oscillations of slow-wave sleep.

Cutting Edge: T Cells from Aged Mice Are Resistant to Depletion Early During Virus Infection

Aging is associated with decreased expansion of T cells upon stimulation. In young mice, infection induces a transient T cell depletion followed by the development of an Ag-specific T cell response that controls the infection. We found that T cells were depleted early after infection with E55 + murine leukemia retrovirus in young, but not aged, mice. Adoptive transfer experiments showed donor T cells of young, but not aged, mice were depleted due to apoptosis in various tissues of young recipients. However, T cells of neither young nor aged donors were depleted in aged recipients. These results indicate that both environmental and intrinsic cellular properties limit depletion of T cells of aged mice and suggest a novel explanation for the decreased T cell response associated with aging.