Satellite microglia display spontaneous electrical activity uncorrelated with activity of the attached neuron

Microglia are innate immune cells of the brain. We have studied a subpopulation of microglia, called satellite microglia. This cell type is defined by a close morphological soma-to-soma association with a neuron, indicative of a direct functional interaction. Indeed, ultrastructural analysis revealed closely attached plasma membranes of satellite microglia and neurons. However, we found no apparent morphological specializations of the contact and biocytin injection into satellite microglia showed no dye-coupling with the apposed neuron or any other cell. Likewise, evoked local field potentials or action potentials and postsynaptic potentials of the associated neuron did not lead to any transmembrane currents or non-capacitive changes in the membrane potential of the satellite microglia in the cortex and hippocampus. Both satellite and non-satellite microglia, however, showed spontaneous transient membrane depolarizations which were not correlated with neuronal activity. These events could be divided into fast and slow rising depolarisations, which exhibited different characteristics in satellite and non-satellite microglia. Fast and slow rising potentials differed with regard to voltage dependence. The frequency of these events was not affected by application of TTX, but fast rising event frequency decreased after application of GABA. We conclude that microglial cells show spontaneous electrical activity uncorrelated with the activity of adjacent neurons

Axonal gap junctions between principal neurons: a novel source of network oscillations, and perhaps epileptogenesis

We hypothesized in 1998 that gap junctions might be located between the axons of principal hippocampal neurons, based on the shape of spikelets (fast prepotentials), occurring during gap junction-mediated very fast (to approximately 200 Hz) network oscillations in vitro. More recent electrophysiological, pharmacological and dye-coupling data indicate that axonal gap junctions exist; so far, they appear to be located about 100 microm from the soma, in CA1 pyramidal neurons. Computer modeling and theory predict that axonal gap junctions can lead to very fast network oscillations under three conditions: a) there are spontaneous axonal action potentials; b) the number of gap junctions in the network is neither too low (not less than to approximately 1.5 per cell on average), nor too high (not more than to approximately 3 per cell on average); c) action potentials can cross from axon to axon via gap junctions. Simulated oscillations resemble biological ones, but condition (c) remains to be demonstrated directly. Axonal network oscillations can, in turn, induce oscillatory activity in larger neuronal networks, by a variety of mechanisms. Axonal networks appear to underlie in vivo ripples (to approximately 200 Hz field potential oscillations superimposed on physiological sharp waves), to drive gamma (30-70 Hz) oscillations that appear in the presence of carbachol, and to initiate certain types of ictal discharge. If axonal gap junctions are important for seizure initiation in humans, there could be practical consequences for antiepileptic therapy: at least one gap junction-blocking compound, carbenoxolone, is already in clinical use (for treatment of ulcer disease), and it crosses the blood-brain barrier

GABA<inf>B</inf>R-dependent long-term depression at hippocampal synapses between CB1-positive interneurons and CA1 pyramidal cells

© 2016 Jappy, Valiullina, Draguhn and Rozov.Activity induced long lasting modifications of synaptic efficacy have been extensively studied in excitatory synapses, however, long term plasticity is also a property of inhibitory synapses. Inhibitory neurons in the hippocampal CA1 region can be subdivided according to the compartment they target on the pyramidal cell. Some interneurons preferentially innervate the perisomatic area and axon hillock of the pyramidal cells while others preferentially target dendritic branches and spines. Another characteristic feature allowing functional classification of interneurons is cell type specific expression of different neurochemical markers and receptors. In the hippocampal CA1 region, nearly 90% of the interneurons expressing cannabinoid type 1 receptors (CB1R) also express cholecystokinin (CCK). Therefore, the functional presence of CB1 receptors can be used for identification of the inhibitory input from CCK positive (CCK+) interneurons to CA1 pyramidal cells. The goal of this study was to explore the nature of long term plasticity at the synapses between interneurons expressing CB1 Rs (putative CCK+) and pyramidal neurons in the CA1 region of the hippocampus in vitro. We found that theta burst stimulation triggered robust long-term depression (LTD) at this synapse. The locus of LTD induction was postsynaptic and required activation of GABAb receptors. We also showed that LTD at this synaptic connection involves GABAbR- dependent suppression of adenylyl cyclase and consequent reduction of PKA activity. In this respect. CB1+ to pyramidal cell synapses differ from the majority of the other hippocampal inhibitory connections where theta burst stimulation results in long-term potentiation

GABABR-dependent long-term depression at hippocampal synapses between CB1-positive interneurons and CA1 pyramidal cells

© 2016 Jappy, Valiullina, Draguhn and Rozov. Activity induced long lasting modifications of synaptic efficacy have been extensively studied in excitatory synapses, however, long term plasticity is also a property of inhibitory synapses. Inhibitory neurons in the hippocampal CA1 region can be subdivided according to the compartment they target on the pyramidal cell. Some interneurons preferentially innervate the perisomatic area and axon hillock of the pyramidal cells while others preferentially target dendritic branches and spines. Another characteristic feature allowing functional classification of interneurons is cell type specific expression of different neurochemical markers and receptors. In the hippocampal CA1 region, nearly 90% of the interneurons expressing cannabinoid type 1 receptors (CB1R) also express cholecystokinin (CCK). Therefore, the functional presence of CB1 receptors can be used for identification of the inhibitory input from CCK positive (CCK+) interneurons to CA1 pyramidal cells. The goal of this study was to explore the nature of long term plasticity at the synapses between interneurons expressing CB1 Rs (putative CCK+) and pyramidal neurons in the CA1 region of the hippocampus in vitro. We found that theta burst stimulation triggered robust long-term depression (LTD) at this synapse. The locus of LTD induction was postsynaptic and required activation of GABAb receptors. We also showed that LTD at this synaptic connection involves GABAbR- dependent suppression of adenylyl cyclase and consequent reduction of PKA activity. In this respect. CB1+ to pyramidal cell synapses differ from the majority of the other hippocampal inhibitory connections where theta burst stimulation results in long-term potentiation

GABA-enhanced collective behavior in neuronal axons underlies persistent gamma-frequency oscillations

Gamma (30–80 Hz) oscillations occur in mammalian electroencephalogram in a manner that indicates cognitive relevance. In vitro models of gamma oscillations demonstrate two forms of oscillation: one occurring transiently and driven by discrete afferent input and the second occurring persistently in response to activation of excitatory metabotropic receptors. The mechanism underlying persistent gamma oscillations has been suggested to involve gap-junctional communication between axons of principal neurons, but the precise relationship between this neuronal activity and the gamma oscillation has remained elusive. Here we demonstrate that gamma oscillations coexist with high-frequency oscillations (>90 Hz). High-frequency oscillations can be generated in the axonal plexus even when it is physically isolated from pyramidal cell bodies. They were enhanced in networks by nonsomatic -aminobutyric acid type A (GABAA) receptor activation, were modulated by perisomatic GABAA receptor-mediated synaptic input to principal cells, and provided the phasic input to interneurons required to generate persistent gamma-frequency oscillations. The data suggest that high-frequency oscillations occurred as a consequence of random activity within the axonal plexus. Interneurons provide a mechanism by which this random activity is both amplified and organized into a coherent network rhythm

A role for fast rhythmic bursting neurons in cortical gamma oscillations in vitro

Basic cellular and network mechanisms underlying gamma frequency oscillations (30–80 Hz) have been well characterized in the hippocampus and associated structures. In these regions, gamma rhythms are seen as an emergent property of networks of principal cells and fast-spiking interneurons. In contrast, in the neocortex a number of elegant studies have shown that specific types of principal neuron exist that are capable of generating powerful gamma frequency outputs on the basis of their intrinsic conductances alone. These fast rhythmic bursting (FRB) neurons (sometimes referred to as "chattering" cells) are activated by sensory stimuli and generate multiple action potentials per gamma period. Here, we demonstrate that FRB neurons may function by providing a large-scale input to an axon plexus consisting of gap-junctionally connected axons from both FRB neurons and their anatomically similar counterparts regular spiking neurons. The resulting network gamma oscillation shares all of the properties of gamma oscillations generated in the hippocampus but with the additional critical dependence on multiple spiking in FRB cells

The relative contribution of nmdars to excitatory postsynaptic currents is controlled by ca²⁺-induced inactivation

© 2016 Valiullina, Zakharova, Mukhtarov, Draguhn, Burnashev and Rozov.NMDA receptors (NMDARs) are important mediators of excitatory synaptic transmission and plasticity. A hallmark of these channels is their high permeability to Ca2+. At the same time, they are themselves inhibited by the elevation of intracellular Ca2+ concentration. It is unclear however, whether the Ca2+ entry associated with single NMDAR mediated synaptic events is sufficient to self-inhibit their activation. Such auto-regulation would have important effects on the dynamics of synaptic excitation in several central neuronal networks. Therefore, we studied NMDAR-mediated synaptic currents in mouse hippocampal CA1 pyramidal neurons. Postsynaptic responses to subthreshold Schaffer collateral stimulation depended strongly on the absence or presence of intracellular Ca2+ buffers. Loading of pyramidal cells with exogenous Ca2+ buffers increased the amplitude and decay time of NMDAR mediated EPSCs (EPSPs) and prolonged the time window for action potential (AP) generation. Our data indicate that the Ca2+ influx mediated by unitary synaptic events is sufficient to produce detectable self-inhibition of NMDARs even at a physiological Mg2+ concentration. Therefore, the contribution of NMDARs to synaptic excitation is strongly controlled by both previous synaptic activity as well as by the Ca2+ buffer capacity of postsynaptic neurons

Layer specific development of neocortical pyramidal to fast spiking cell synapses

© 2016 Voinova, Valiullina, Zakharova, Mukhtarov, Draguhn and Rozov. All cortical neurons are engaged in inhibitory feedback loops which ensure excitation-inhibition balance and are key elements for the development of coherent network activity. The resulting network patterns are strongly dependent on the strength and dynamic properties of these excitatory-inhibitory loops which show pronounced regional and developmental diversity. Therefore we compared the properties and postnatal maturation of two different synapses between rat neocortical pyramidal cells (layer 2/3 and layer 5, respectively) and fast spiking (FS) intemeurons in the corresponding layer. At P14, both synapses showed synaptic depression upon repetitive activation. Synaptic release properties between layer 2/3 pyramidal cells and FS cells were stable from P14 to P28. In contrast, layer 5 pyramidal to FS cell connections showed a significant increase in paired pulse ratio by P28. Presynaptic calcium dynamics also changed at these synapses, including sensitivity to exogenously loaded calcium buffers and expression of presynaptic calcium channel subtypes. These results underline the large variety of properties at different, yet similar, synapses in the neocortex. They also suggest that postnatal maturation of the brain goes along with increasing differences between synaptically driven network activity in layer 5 and layer 2/3

The relative contribution of nmdars to excitatory postsynaptic currents is controlled by ca2+-induced inactivation

© 2016 Valiullina, Zakharova, Mukhtarov, Draguhn, Burnashev and Rozov. NMDA receptors (NMDARs) are important mediators of excitatory synaptic transmission and plasticity. A hallmark of these channels is their high permeability to Ca2+. At the same time, they are themselves inhibited by the elevation of intracellular Ca2+ concentration. It is unclear however, whether the Ca2+ entry associated with single NMDAR mediated synaptic events is sufficient to self-inhibit their activation. Such auto-regulation would have important effects on the dynamics of synaptic excitation in several central neuronal networks. Therefore, we studied NMDAR-mediated synaptic currents in mouse hippocampal CA1 pyramidal neurons. Postsynaptic responses to subthreshold Schaffer collateral stimulation depended strongly on the absence or presence of intracellular Ca2+ buffers. Loading of pyramidal cells with exogenous Ca2+ buffers increased the amplitude and decay time of NMDAR mediated EPSCs (EPSPs) and prolonged the time window for action potential (AP) generation. Our data indicate that the Ca2+ influx mediated by unitary synaptic events is sufficient to produce detectable self-inhibition of NMDARs even at a physiological Mg2+ concentration. Therefore, the contribution of NMDARs to synaptic excitation is strongly controlled by both previous synaptic activity as well as by the Ca2+ buffer capacity of postsynaptic neurons