Exceptions to Cajal's neuron theory: communicating synapses

Ultrastructural images of some neurons and their synaptic connections, belonging to the nucleus of the periaqueductal grey substance in the domestic cat mesencephalon, are shown. The finding that some axosomatic synapses showed an open communication between the pre- and postsynaptic portion attracted our attention. In this way a continuity is made between the presynaptic bouton of one neuron (axon) and the postsynaptic portion of the other (neuronal soma). Synapses having these interneuronal communications could be denominated communicating synapses. Accepting Cajal's neuron theory and his law of neuronal independence, it is very difficult to interpret these images. We wonder if this type of communicating synapses could be the exception that proves the rule of the neuron independence.     

The self-tuning neuron: synaptic scaling of excitatory synapses

Homeostatic synaptic scaling is a form of synaptic plasticity that adjusts the strength of all of a neuron's excitatory synapses up or down to stabilize firing. Current evidence suggests that neurons detect changes in their own firing rates through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of glutamate receptors at synaptic sites. Additional mechanisms may allow local or network-wide changes in activity to be sensed through parallel pathways, generating a nested set of homeostatic mechanisms that operate over different temporal and spatial scales.     

Discrete wave mechanism of integral activity in heterogenic neuron synapses]

On the basis of the conception of the discrete wave mechanism for the integration of heterogeneous neuron elements, a hypothesis was put forward that neuron excitation propagates as waves of changes in the conformational states of neuron membrane lipids. A mathematical model was constructed, which confirms the wave mode of excitation propagation. The model enables one to consider the integration of postsynaptic potentials as a process of wave interference. It was assumed that the training of neuron elements can be considered as a process of nonuniform distribution of lipids.     

Development of unified statistical potentials describing protein-protein interactions

A residue-based and a heavy atom-based statistical pair potential are developed for use in assessing the strength of protein-protein interactions. To ensure the quality of the potentials, a nonredundant, high-quality dimer database is constructed. The protein complexes in this dataset are checked by a literature search to confirm that they form multimers, and the pairwise amino acid preference to interact across a protein-protein interface is analyzed and pair potentials constructed. The performance of the residue-based potentials is evaluated by using four jackknife tests and by assessing the potentials' ability to select true protein-protein interfaces from false ones. Compared to potentials developed for monomeric protein structure prediction, the interdomain potential performs much better at distinguishing protein-protein interactions. The potential developed from homodimer interfaces is almost the same as that developed from heterodimer interfaces with a correlation coefficient of 0.92. The residue-based potential is well suited for genomic scale protein interaction prediction and analysis, such as in a recently developed threading-based algorithm, MULTIPROSPECTOR. However, the more time-consuming atom-based potential performs better in identifying near-native structures from docking generated decoys.     

Models describing the kinetics of ribulose biphosphate carboxylase-oxygenase.

Equations are developed to describe the reactions of ribulose 1,5-biphosphate carboxylase—oxygenase with ribulose biphosphate (RuP₂), carbon dioxide, and oxygen. It is predicted that at the high concentrations of enzyme sites found in vivo there will be a large proportion of the total RuP₂ bound to the enzyme. The kinetic characteristics of the in vivo reactions with RuP₂ are predicted to be analogous to those which would occur in the presence of a tight-binding substrate. Equations are developed which are applicable when the enzyme is only partially activated by CO₂ and Mg²⁺. The response of carboxylase velocity to CO₂ concentration is sigmoidal when Mg²⁺ concentration is low.     

Location-dependent excitatory synaptic interactions in pyramidal neuron dendrites

Neocortical pyramidal neurons (PNs) receive thousands of excitatory synaptic contacts on their basal dendrites. Some act as classical driver inputs while others are thought to modulate PN responses based on sensory or behavioral context, but the biophysical mechanisms that mediate classical-contextual interactions in these dendrites remain poorly understood. We hypothesized that if two excitatory pathways bias their synaptic projections towards proximal vs. distal ends of the basal branches, the very different local spike thresholds and attenuation factors for inputs near and far from the soma might provide the basis for a classical-contextual functional asymmetry. Supporting this possibility, we found both in compartmental models and electrophysiological recordings in brain slices that the responses of basal dendrites to spatially separated inputs are indeed strongly asymmetric. Distal excitation lowers the local spike threshold for more proximal inputs, while having little effect on peak responses at the soma. In contrast, proximal excitation lowers the threshold, but also substantially increases the gain of distally-driven responses. Our findings support the view that PN basal dendrites possess significant analog computing capabilities, and suggest that the diverse forms of nonlinear response modulation seen in the neocortex, including uni-modal, cross-modal, and attentional effects, could depend in part on pathway-specific biases in the spatial distribution of excitatory synaptic contacts onto PN basal dendritic arbors.     

Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli

Midbrain dopamine (DA) neurons are not homogeneous but differ in their molecular properties and responses to external stimuli. We examined whether the modulation of excitatory synapses on DA neurons by rewarding or aversive stimuli depends on the brain area to which these DA neurons project. We identified DA neuron subpopulations in slices after injection of "Retrobeads" into single target areas of adult mice and found differences in basal synaptic properties. Administration of cocaine selectively modified excitatory synapses on DA cells projecting to nucleus accumbens (NAc) medial shell while an aversive stimulus selectively modified synapses on DA cells projecting to medial prefrontal cortex. In contrast, synapses on DA neurons projecting to NAc lateral shell were modified by both rewarding and aversive stimuli, which presumably reflects saliency. These results suggest that the mesocorticolimbic DA system may be comprised of three anatomically distinct circuits, each modified by distinct aspects of motivationally relevant stimuli.     

Homeostatic matching and nonlinear amplification at identified central synapses

Here we describe the properties of a synapse in the Drosophila antennal lobe and show how they can explain certain sensory computations in this brain region. The synapse between olfactory receptor neurons (ORNs) and projection neurons (PNs) is very strong, reflecting a large number of release sites and high release probability. This is likely one reason why weak ORN odor responses are amplified in PNs. Furthermore, the amplitude of unitary synaptic currents in a PN is matched to the size of its dendritic arbor. This matching may compensate for a lower input resistance of larger dendrites to produce uniform depolarization across PN types. Consistent with this idea, a genetic manipulation that lowers input resistance increases unitary synaptic currents. Finally, strong stimuli produce short-term depression at this synapse. This helps explain why PN odor responses are transient, and why strong ORN odor responses are not amplified as powerfully as weak responses.     

Microglial interactions with synapses are modulated by visual experience

Microglia are the immune cells of the brain. In the absence of pathological insult, their highly motile processes continually survey the brain parenchyma and transiently contact synaptic elements. Aside from monitoring, their physiological roles at synapses are not known. To gain insight into possible roles of microglia in the modification of synaptic structures, we used immunocytochemical electron microscopy, serial section electron microscopy with three-dimensional reconstructions, and two-photon in vivo imaging to characterize microglial interactions with synapses during normal and altered sensory experience, in the visual cortex of juvenile mice. During normal visual experience, most microglial processes displayed direct apposition with multiple synapse-associated elements, including synaptic clefts. Microglial processes were also distinctively surrounded by pockets of extracellular space. In terms of dynamics, microglial processes localized to the vicinity of small and transiently growing dendritic spines, which were typically lost over 2 d. When experience was manipulated through light deprivation and reexposure, microglial processes changed their morphology, showed altered distributions of extracellular space, displayed phagocytic structures, apposed synaptic clefts more frequently, and enveloped synapse-associated elements more extensively. While light deprivation induced microglia to become less motile and changed their preference of localization to the vicinity of a subset of larger dendritic spines that persistently shrank, light reexposure reversed these behaviors. Taken together, these findings reveal different modalities of microglial interactions with synapses that are subtly altered by sensory experience. These findings suggest that microglia may actively contribute to the experience-dependent modification or elimination of a specific subset of synapses in the healthy brain.     

Loss of correlated motor neuron activity during synaptic competition at developing neuromuscular synapses

During late stages of neural development, synaptic circuitry is edited by neural activity. At neuromuscular synapses, the transition from multiple to single innervation is modulated by the relative pattern of activity among inputs competing for innervation of the same muscle fiber. While experimental perturbations of activity result in marked changes in the timing of neuromuscular synaptic competition, little is known about the patterns of activity present during normal development. Here, we report the temporal patterning of motor unit activity in the soleus muscle of awake, behaving neonatal mice, and that patterning is modulated by gap-junctional coupling. Our work suggests that neuromuscular synaptic competition is modulated by surprisingly low levels of activity and may be triggered by the disappearance of temporally correlated activity among inputs competing for innervation of the same muscle fiber.     

A two-variable model of somatic-dendritic interactions in a bursting neuron

We present a two-variable delay-differential-equation model of a pyramidal cell from the electrosensory lateral line lobe of a weakly electric fish that is capable of burst discharge. It is a simplification of a six-dimensional ordinary differential equation model for such a cell whose bifurcation structure has been analyzed (Doiron et al., J. Comput. Neurosci., 12, 2002). We have modeled the effects of back-propagating action potentials by a delay, and use an integrate-and-fire mechanism for action potential generation. The simplicity of the model presented here allows one to explicitly derive a two-dimensional map for successive interspike intervals, and to analytically investigate the effects of time-dependent forcing on such a model neuron. Some of the effects discussed include ‘burst excitability’, the creation of resonance tongues under periodic forcing, and stochastic resonance. We also investigate the effects of changing the parameters of the model.     

Intracellular nonlinear frequency response measurements in the cockroach tactile spine neuron

The threshold of the cockroach tactile neuron increases strongly with depolarization by a process involving at least two time constants. This effect is probably responsible for the rapid and complete adaptation of the neuron's response to step inputs. A technique for intracellular recording and stimulation of the neuron has recently been established and this allows direct observation of the dynamic response of the neuronal encoder. A white noise stimulus was used to modulate the membrane potential of the neuron. The first-order frequency response function between membrane potential and action potential discharge could be explained by a variable threshold model with two time constants. Second-order frequency response functions could be accounted for by a Wiener cascade model. The dynamic nonlinear behavior of the encoder can therefore be explained by a unidirectional threshold which increases linearly and dynamically with membrane potential.     

Ultrastructural changes of rat cortical neuron synapses for isolated and combined microapplications of transmitters

The ultrastructure of the presynaptic and postsynaptic components of the axo-dendritic synapses of layer V in the sensorimotor region of the rat neocortex is compared for microlonophoretic applications of 1-glutamate and norepinephrine, as well as for combined and successive administrations of these substances. A reliable increase is noted in the width of the postsynaptic density for combined electrophoresis of glutamate and norepinephrine, and a decrease in the number of synaptic vesicles at the terminals for applications of norepinephrine and combined and isolated administration of both transmitters. The results are discussed as an index of the modulating effect of norepinephrine on other neurotransmitter systems.M. V. Lomonosov State University, Moscow. Translated from Neirofiziologiya, Vol. 17, No. 4, pp. 476–481, July–August, 1985.