Trigger regime of the functioning of the synaptic channel

With a nonlinear model describing the dynamics of biochemical reactions occurring in a synapse, it is shown that, as periodic step-like pulses pass through a synaptic channel, it operates in a trigger mode. Pulse transmission through the channel is associated with a change of the stationary point of the corresponding dynamic system as compared with the unexcited state of the synapse. As a result, the system periodically evolves between two stable stationary states.     

Mechanisms underlying induction and maintenance of long-term potentiation in the hippocampus

Long-term potentiation (LTP) in the hippocampus is accompanied by a number of changes on both sides of the synapse. It is now generally considered that the trigger for initiating LTP is the entry of calcium into the postsynaptic area through the NMDA-associated channel while the mechanism(s) underlying the maintenance of LTP are less well understood and probably involve contributions from both sides of the synapse.     

Keeping the balance

How we see our environment is the result of a multi-level, parallel processing effort by the central nervous system. This computation is initiated within the retina at the very first synapse in the visual pathway – the photoreceptor ribbon synapse. Two recent studies shed light on the critical role of balanced calcium channel activity in maturation of this highly specialized synapse.^{1, 2}     

Ion-conformational interaction and charge transport through channels of biological membranes

This work proposes a theory of charge transport through channels in biological membranes, based on ion flow interaction with charged groups of protein macromolecules that form the channel. Displacements of the groups are due to conformational changes of the protein molecule, the relaxation times of which are much larger than the average time of ion ocurrence in the channel. Ion flow is assumed to depend on the conformational changes and vice-versa. The resulting self-organizing ion-conformational system is described by a set of nonlinear differential equations for conformational variables and average occupancy of the channel by ions. The system exhibits multistable behaviour in a certain range of control parameters (potential difference, input ion flow). The stationary states of the system may be identified with the states of discrete conductivity of the ionic channels.     

The study of role of membrane-bound Ca2+ in the regulation of relationship between neuron and glia during rhythmic excitation

The role of membrane-bound Ca2+ in the regulation of Ca2+ transport through voltage-gated Ca2+ channel, and NMDA-glutamate and n-acetylcholine receptors upon interaction of a neuron with glia during rhythmic excitation was studied. It was found that the redistribution and transport of Ca2+ play a crucial role in the conductance of rhythmic excitation in both a "neuron-neuron" system and the processes providing the maintenance of a stationary level of rhythmic excitation in the system "neuron-glia".     

Presynaptic N-type calcium channels regulate synaptic growth

Voltage-gated calcium channels couple changes in membrane potential to neuronal functions regulated by calcium, including neurotransmitter release. Here we report that presynaptic N-type calcium channels not only control neurotransmitter release but also regulate synaptic growth at Drosophila neuromuscular junctions. In a screen for behavioral mutants that disrupt synaptic transmission, an allele of the N-type calcium channel locus (Dmca1A) was identified that caused synaptic undergrowth. The underlying molecular defect was identified as a neutralization of a charged residue in the third S4 voltage sensor. RNA interference reduction of N-type calcium channel expression also reduced synaptic growth. Hypomorphic mutations in syntaxin-1A or n-synaptobrevin, which also disrupt neurotransmitter release, did not affect synapse proliferation at the neuromuscular junction, suggesting calcium entry through presynaptic N-type calcium channels, not neurotransmitter release per se, is important for synaptic growth. The reduced synapse proliferation in Dmca1A mutants is not due to increased synapse retraction but instead reflects a role for calcium influx in synaptic growth mechanisms. These results suggest N-type channels participate in synaptic growth through signaling pathways that are distinct from those that mediate neurotransmitter release. Linking presynaptic voltage-gated calcium entry to downstream calcium-sensitive synaptic growth regulators provides an efficient activity-dependent mechanism for modifying synaptic strength.     

Influence of mediator diffusion on trigger mode of a synapse

The model of postsynaptic membrane activation is proposed in the paper. This model takes into account inhomogeneity of mediator’s space distribution in the region of the synaptic cleft as well as nonlinear nature of interaction between the mediator and receptors on the postsynaptic membrane. Based on equations of this model stationary solutions are calculated for mediator distribution in the synaptic cleft and the number of activated receptors. Kinetics of reactions for activation and deactivation of receptors is analyzed within the concept of a trigger mode of the synapse. It is shown that activation-deactivation processes and redistribution of the mediator in the cleft can be interpreted as successive transitions between two stationary states of the system. Time of transitions between these states is found and its dependence on system parameters (in particular on the width of the synaptic cleft) is analyzed.     

Loss of extrasynaptic channel modulation by protein kinase C underlies the selection of serotonin responses in an identified leech neuron.

Pressure-sensitive (P) neurons contacted by serotonergic Retzius (R) neurons of the leech in culture selectively reduce a protein kinase C (PKC)-dependent cation response to serotonin and are innervated by the inhibitory, Cl(-)-dependent synapse seen in vivo. We have examined whether the reduction of extrasynaptic cation channel modulation is due to changes in sensitivity of the channels to second messenger. In inside-out membrane patches from single, uncontacted P cells in culture, cation channel activity was increased by rat brain PKC and cofactors. In contrast, the activity of cation channels in patches isolated from P cells paired with R cells was unaffected by PKC. These results demonstrate the loss of extrasynaptic channel modulation by PKC during synapse formation.     

Neuromodulatory changes in short-term synaptic dynamics may be mediated by two distinct mechanisms of presynaptic calcium entry

Although synaptic output is known to be modulated by changes in presynaptic calcium channels, additional pathways for calcium entry into the presynaptic terminal, such as non-selective channels, could contribute to modulation of short term synaptic dynamics. We address this issue using computational modeling. The neuropeptide proctolin modulates the inhibitory synapse from the lateral pyloric (LP) to the pyloric dilator (PD) neuron, two slow-wave bursting neurons in the pyloric network of the crab Cancer borealis. Proctolin enhances the strength of this synapse and also changes its dynamics. Whereas in control saline the synapse shows depression independent of the amplitude of the presynaptic LP signal, in proctolin, with high-amplitude presynaptic LP stimulation the synapse remains depressing while low-amplitude stimulation causes facilitation. We use simple calcium-dependent release models to explore two alternative mechanisms underlying these modulatory effects. In the first model, proctolin directly targets calcium channels by changing their activation kinetics which results in gradual accumulation of calcium with low-amplitude presynaptic stimulation, leading to facilitation. The second model uses the fact that proctolin is known to activate a non-specific cation current I _MI . In this model, we assume that the MI channels have some permeability to calcium, modeled to be a result of slow conformation change after binding calcium. This generates a gradual increase in calcium influx into the presynaptic terminals through the modulatory channel similar to that described in the first model. Each of these models can explain the modulation of the synapse by proctolin but with different consequences for network activity.     

Gating of Ca2+-activated K+ channels controls fast inhibitory synaptic transmission at auditory outer hair cells

Fast inhibitory synaptic transmission in the central nervous system is mediated by ionotropic GABA or glycine receptors. Auditory outer hair cells present a unique inhibitory synapse that uses a Ca2+-permeable excitatory acetylcholine receptor to activate a hyperpolarizing potassium current mediated by small conductance calcium-activated potassium (SK) channels. It is shown here that unitary inhibitory postsynaptic currents at this synapse are mediated by SK2 channels and occur rapidly, with rise and decay time constants of approximately 6 ms and approximately 30 ms, respectively. This time course is determined by the Ca2+ gating of SK channels rather than by the changes in intracellular Ca2+. The results demonstrate fast coupling between an excitatory ionotropic neurotransmitter receptor and an inhibitory ion channel and imply rapid, localized changes in subsynaptic calcium levels.     

TRPV1通道在中枢神经系统中的功能

TRPV1（transient receptor potential vanilloid 1）是在机体广泛分布的非选择性阳离子通道,能被氢离子、高温以及其它内源性和外源性配体激活.其在外周神经系统中主要参与伤害性高温的感受以及痛觉过敏等生理机制.TRPV1在中枢神经系统中功能的研究进展主要体现在突触传递,体温调节,痛觉的调制和细胞凋亡等方面.TRPV1的激活降低突触前谷氨酸的释放及增强已存在的突触后AMPA受体的作用,从而增强了突触传递效能.外周的TRPV1通过激活能够抑制血管的收缩和生热作用,从而抑制体温的升高,当TRPV1被阻断时就发生体温过高,而TRPV1体温调节的中枢作用机制可能是通过直接作用于体温调节中枢.脑干的痛觉调制环路的激活TRPV1可以引起谷氨酸盐的释放,进而激活突触后I类mGlu受体以及NMDA受体,从而起到镇痛的功能.另外近年发现TRPV1在中枢也参与呕吐、呼吸、心率及血压的调节.     

Loss of channel modulation by transmitter and protein kinase C during innervation of an identified leech neuron.

When serotonergic Retzius (R) neurons of the leech contact pressure-sensitive (P) neurons in culture, P cells selectively lose a protein kinase C-dependent cationic response to serotonin and the R cell reforms the inhibitory, chloride-dependent synapse seen in vivo. In P cells not contacted by R cells, cell-attached patches contained single cation channels sensitive to serotonin and phorbol ester with characteristic properties and high incidence (present in about one-half of the patches). P cells paired with R cells had a cation channel with similar biophysical properties and incidence, but channel activity was not stimulated by serotonin and phorbol ester. These results suggest that the early clearing of the non-synaptic (excitatory) response to serotonin is due to the loss of activation by protein kinase C (and not the number) of cation channels as a prelude to inhibitory synapse formation.     

Synapse‐dependent and independent mechanisms of thalamocortical axon branching are regulated by neuronal activity

Axon branching and synapse formation are critical processes for establishing precise circuit connectivity. These processes are tightly regulated by neural activity, but the relationship between them remains largely unclear. We use organotypic coculture preparations to examine the role of synapse formation in the activity‐dependent axon branching of thalamocortical (TC) projections. To visualize TC axons and their presynaptic sites, two plasmids encoding DsRed and EGFP‐tagged synaptophysin (SYP‐EGFP) were cotransfected into a small number of thalamic neurons. Time‐lapse imaging of individual TC axons showed that most branches emerged from SYP‐EGFP puncta, indicating that synapse formation precedes emergences of axonal branches. We also investigated the effects of neuronal activity on axon branching and synapse formation by manipulating spontaneous firing activity of thalamic cells. An inward rectifying potassium channel, Kir2.1, and a bacterial voltage‐gated sodium channel, NaChBac, were used to suppress and promote firing activity, respectively. We found suppressing neural activity reduced both axon branching and synapse formation. In contrast, increasing neural activity promoted only axonal branch formation. Time‐lapse imaging of NaChBac‐expressing cells further revealed that new branches frequently appeared from the locations other than SYP‐EGFP puncta, indicating that enhancing activity promotes axonal branch formation due to an increase of branch emergence at nonsynaptic sites. These results suggest that presynaptic locations are hotspots for branch emergence, and that frequent firing activity can shift branch emergence to a synapse‐independent process. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 323–336, 2016     

An RNAi-based approach identifies molecules required for glutamatergic and GABAergic synapse development

We report the results of a genetic screen to identify molecules important for synapse formation and/or maintenance. siRNAs were used to decrease the expression of candidate genes in neurons, and synapse development was assessed. We surveyed 22 cadherin family members and demonstrated distinct roles for cadherin-11 and cadherin-13 in synapse development. Our screen also revealed roles for the class 4 Semaphorins Sema4B and Sema4D in the development of glutamatergic and/or GABAergic synapses. We found that Sema4D affects the formation of GABAergic, but not glutamatergic, synapses. Our screen also identified the activity-regulated small GTPase Rem2 as a regulator of synapse development. A known calcium channel modulator, Rem2 may function as part of a homeostatic mechanism that controls synapse number. These experiments establish the feasibility of RNAi screens to characterize the mechanisms that control mammalian neuronal development and to identify components of the genetic program that regulate synapse formation and/or maintenance.     

A positive feedback synapse from retinal horizontal cells to cone photoreceptors

Cone photoreceptors and horizontal cells (HCs) have a reciprocal synapse that underlies lateral inhibition and establishes the antagonistic center-surround organization of the visual system. Cones transmit to HCs through an excitatory synapse and HCs feed back to cones through an inhibitory synapse. Here we report that HCs also transmit to cone terminals a positive feedback signal that elevates intracellular Ca(2+) and accelerates neurotransmitter release. Positive and negative feedback are both initiated by AMPA receptors on HCs, but positive feedback appears to be mediated by a change in HC Ca(2+), whereas negative feedback is mediated by a change in HC membrane potential. Local uncaging of AMPA receptor agonists suggests that positive feedback is spatially constrained to active HC-cone synapses, whereas the negative feedback signal spreads through HCs to affect release from surrounding cones. By locally offsetting the effects of negative feedback, positive feedback may amplify photoreceptor synaptic release without sacrificing HC-mediated contrast enhancement.     

The twisting elevator mechanism of glutamate transporters reveals the structural basis for the dual transport-channel functions

Glutamate transporters facilitate the removal of this excitatory neurotransmitter from the synapse. Increasing evidence indicates that this process is linked to intrinsic chloride channel activity that is thermodynamically uncoupled from substrate transport. A recent cryo-EM structure of Glt_Ph – an archaeal homolog of the glutamate transporters – in an open channel state has shed light on the structural basis for channel opening formed at the interface of two domains within the transporter which is gated by two clusters of hydrophobic residues. These transporters cycle through several conformational states during the transport process, including the chloride conducting state, which appears to be stabilised by protein–membrane interactions and membrane deformation. Several point mutations that perturb the chloride conductance can have detrimental effects and are linked to the pathogenesis of the neurological disorder, episodic ataxia type 6.     

Ribbon synapses of the retina

Vision is a highly complex task that involves several steps of parallel information processing in various areas of the central nervous system. Complex processing of visual signals occurs as early as at the retina, the first stage in the visual system. Various aspects of visual information are transmitted in parallel from the photoreceptors (the input neurons of the retina) through their interconnecting bipolar cells to the ganglion cells (the output neurons). Photoreceptors and bipolar cells transfer information via the release of the neurotransmitter glutamate at a specialized synapse, the ribbon synapse. Although known from early days of electron microscopy, the precise functioning of ribbon synapses has yet to be explained. In this review, we highlight recent advances towards understanding the molecular composition and function of this enigmatic synapse.This study was supported by a grant from the Deutsche Forschungsgemeinschaft (BR 1643/4-1) to J.H.B.     

The role of glial cells in synapse elimination

Excessive synapses generated during early development are eliminated extensively to form functionally mature neural circuits. Synapses in juvenile and mature brains are highly dynamic, and undergo remodeling processes through constant formation and elimination of dendritic spines. Although neural activity has been implicated in initiating the synapse elimination process cell-autonomously, the cellular and molecular mechanisms that transduce changes in correlated neural activity into structural changes in synapses are largely unknown. Recently, however, new findings provide evidence that in different species, glial cells, non-neuronal cell types in the nervous system are crucial in eliminating neural debris and unwanted synapses through phagocytosis. Glial cells not only clear fragmented axons and synaptic debris produced during synapse elimination, but also engulf unwanted synapses thereby actively promoting synapse elimination non-cell autonomously. These new findings support the important role of glial cells in the formation and maintenance of functional neural circuits in development as well as in adult stages and neurodegenerative diseases.     

Formation of charge-exchange ion flows near the exit from the stationary plasma thruster acceleration channel

Ion currents onto the exit plane of the acceleration channel of a stationary plasma thruster model were measured using electrostatic probes the collecting surfaces of which could be oriented either upstream or downstream with respect to the thruster plume. Using the results of measurements, the so-called “back” flows of charge-exchange ions onto the exit plane are estimated. It is shown that the back ion flows are the most intense in the close vicinity of the thruster, but do not exceed 0.6% of the total ion flow from the thruster. The formation of steady-state ion flows near the exit from the acceleration channel of a stationary plasma thruster is simulated numerically by using a three-dimensional kinetic model that describes the dynamics of ions and neutral atoms exhausting from the acceleration channel and produced in the thruster plume and takes into account resonance charge exchange of ions with neutral atoms. The distribution of the back ion current density in the exit plane is determined. The effect of the flow rate of the working gas through the cathode on the distributions of the neutral atom density and charge-exchange ion flows is demonstrated. The obtained results can be used to analyze the effect of the thruster plume on the charge state of the surfaces located in the vicinity of the thruster.