Dendritic spikes and activity-dependent synaptic plasticity

Whereas the regenerative nature of action potential conduction in axons has been known since the late 1940s, neuronal dendrites have been considered as passive cables transferring incoming synaptic activity to the soma. The relatively recent discovery that neuronal dendrites contain active conductances has revolutionized our view of information processing in neurons. In many neuronal cell types, sodium action potentials initiated at the axon initial segment can back-propagate actively into the dendrite thereby serving, for the dendrite, as an indicator of the output activity of the neuron. In addition, the dendrites themselves can initiate action-potential-like regenerative responses, so-called dendritic spikes, that are mediated either by the activation of sodium, calcium, and/or N-methyl-D-aspartate receptor channels. Here, we review the recent experimental and theoretical evidence for a role of regenerative dendritic activity in information processing within neurons and, especially, in activity-dependent synaptic plasticity.     

Action potential generation by turtle cortical neurons. Dendritic and somatic spikes

Action potentials of neurons of the turtle general cortex and the pattern of their generation were studied by an intracellular recording method. Besides the complete action potential, the cells also generate partial spikes of varied amplitude which compose the complete action potential. The threshold of generation and the discrete amplitude of each partial spike are not strictly constant but they fluctuate gradually and spontaneously within certain limits without any change in membrane potential of the cell. Somatic and dendritic spikes are distinguished. The trigger zones of the latter are located at various distances from the soma. During orthodromic activation of cortical neurons dendritic spikes are generated consecutively and spread to the some electrotonically with a decrement. They are the immediate cause of generation of the somatic spike.M. V. Lomonovsov Moscow State University. Translated from Neirofiziologiya, Vol. 8, No. 3, pp. 237–242, May–June, 1976.     

Dendritic sodium spikes endow neurons with inverse firing rate response to correlated synaptic activity

Many neurons possess dendrites enriched with sodium channels and are capable of generating action potentials. However, the role of dendritic sodium spikes remain unclear. Here, we study computational models of neurons to investigate the functional effects of dendritic spikes. In agreement with previous studies, we found that point neurons or neurons with passive dendrites increase their somatic firing rate in response to the correlation of synaptic bombardment for a wide range of input conditions, i.e. input firing rates, synaptic conductances, or refractory periods. However, neurons with active dendrites show the opposite behavior: for a wide range of conditions the firing rate decreases as a function of correlation. We found this property in three types of models of dendritic excitability: a Hodgkin-Huxley model of dendritic spikes, a model with integrate and fire dendrites, and a discrete-state dendritic model. We conclude that fast dendritic spikes confer much broader computational properties to neurons, sometimes opposite to that of point neurons.     

Dendritic cell-dependent inhibition of B cell proliferation requires CD22

Recent studies have shown that dendritic cells (DCs) regulate B cell functions. In this study, we report that bone marrow (BM)-derived immature DCs, but not mature DCs, can inhibit BCR-induced proliferation of B cells in a contact-dependent manner. This inhibition is overcome by treatment with BAFF and is dependent on the BCR coreceptor CD22; however, it is not dependent on expression of the CD22 glycan ligand(s) produced by ST6Gal-I sialyltransferase. We found that a second CD22 ligand (CD22L) is expressed on CD11c(+) splenic and BM-derived DCs, which does not contain ST6Gal-I-generated sialic acids and which, unlike the B cell-associated CD22L, is resistant to neuraminidase treatment and sodium metaperiodate oxidation. Examination of splenic and BM B cell subsets in CD22 and ST6Gal-I knockout mice revealed that ST6Gal-I-generated B cell CD22L plays a role in splenic B cell development, whereas the maintenance of long-lived mature BM B cells depends only on CD22 and not on alpha2,6-sialic acids produced by ST6Gal-I. We propose that the two distinct CD22L have different functions. The alpha2,6-sialic acid-containing glycoprotein is important for splenic B cell subset development, whereas the DC-associated ST6Gal-I-independent CD22L may be required for the maintenance of long-lived mature B cells in the BM.     

Neuronal communication: firing spikes with spikes

Spikes of single cortical neurons can exert powerful effects even though most cortical synapses are too weak to fire postsynaptic neurons. A recent study combining single-cell stimulation with population imaging has visualized in?vivo postsynaptic firing in genetically identified target cells. The results confirm predictions from in?vitro work and might help to understand how the brain reads single-neuron activity.     

Crossed inhibition as revealed by cross-correlogram between bilateral homonymous motor unit spikes in man.

Neuromuscular unit (NMU) spikes activated during the tonic vibration reflex (TVR) in man were studied by means of the cross-correlogram test. Those NMUs which preferredly fired at some definite interval with good correlation with vibration were called "locked" spikes. The amount above zero correlation level seen in the cross-correlogram was expressed as ipsilateral "excitatory frequency", Ef. TVR contraction of the ipsilateral quadriceps femoris muscle was stimulated by voluntary contraction of the contralateral quadriceps femoris. I. Cross-correlogram test of the contralateral voluntary NMU spikes with ipsilateral vibration revealed "contralateral inhibitory modulation". Such inhibitory modulation was observed in 24% of the contralateral NMUs during voluntary tracking contraction with visual feed-back and in 22% of NMUs during blind simulated contraction without visual feed-back. The "subtracted" amount, i.e., contralateral inhibitory modulation, was also expressed as the contralateral "inhibitory frequency", If, which was calculated from the indentations of the cross-correlogram. 2. When varied vibratory frequency was applied to the muscle both Ef and If attained their maximum value around an "optimal frequency" of vibration, i.e., 80-95 HZ. 3. The ratio Ef/If was proposed as the reciprocal co-activation ratio which was fairly independent of the change of vibratory frequency. An average value of Ef/If ratio was calculated at 2.2 +/- 0.9 from 19 experiments.     

PhySIC: a veto supertree method with desirable properties

This paper focuses on veto supertree methods; i.e., methods that aim at producing a conservative synthesis of the relationships agreed upon by all source trees. We propose desirable properties that a supertree should satisfy in this framework, namely the non-contradiction property (PC) and the induction property (PI). The former requires that the supertree does not contain relationships that contradict one or a combination of the source topologies, whereas the latter requires that all topological information contained in the supertree is present in a source tree or collectively induced by several source trees. We provide simple examples to illustrate their relevance and that allow a comparison with previously advocated properties. We show that these properties can be checked in polynomial time for any given rooted supertree. Moreover, we introduce the PhySIC method (PHYlogenetic Signal with Induction and non-Contradiction). For k input trees spanning a set of n taxa, this method produces a supertree that satisfies the above-mentioned properties in O(kn(3) + n(4)) computing time. The polytomies of the produced supertree are also tagged by labels indicating areas of conflict as well as those with insufficient overlap. As a whole, PhySIC enables the user to quickly summarize consensual information of a set of trees and localize groups of taxa for which the data require consolidation. Lastly, we illustrate the behaviour of PhySIC on primate data sets of various sizes, and propose a supertree covering 95% of all primate extant genera. The PhySIC algorithm is available at http://atgc.lirmm.fr/cgi-bin/PhySIC.     

Tolerance induction by veto CTLs in the TCR transgenic 2C mouse model. I. Relative reactivity of different veto cells

Several bone marrow cells and lymphocyte subpopulations, known as veto cells, were shown to induce transplantation tolerance across major histocompatibility Ags. Due to the low frequency of the effector T cells against which the veto cells inhibitory activity is aimed, the fate of the effector cells was traditionally followed indirectly by functional limiting dilution assays, which are cumbersome and depend on numerous parameters. In the present study the fate of the effector T cells was monitored directly by FACS, using TCR transgenic mouse CD8(+) T cells in which the transgene is directed against H-2(d) (the 2C model). This assay is validated by demonstrating the potency, selectivity, radiation sensitivity, and contact dependency of anti-third-party CTLs previously demonstrated by the limiting dilution assay. In contrast to veto CTLs, nonactivated CD8(+) T cells lack veto activity. Comparison by FACS in the 2C model revealed a hierarchy of veto cells, in the order of veto CTLs activated NK cells, activated CD4(+) T cells, and activated B cells. The latter cells as well as nonactivated CD4(+) or NK cells were shown to be completely devoid of veto activity.     

Generation and characterization of IL-2-activated veto cells.

The regulation of in vivo cytolytic response is important in a model of murine graft-vs-host disease induced by the injection of parental splenocytes into unirradiated B6D2F1 recipients. Injection of C57BL/6J spleen cells into B6D2F1 recipients results in an acute form of graft-vs-host disease that is characterized by the presence of CTL and suppressor cells, runting, and occasionally death. In contrast, injection of DBA/2J spleen cells into B6D2F1 recipients results in a chronic form of graft-vs-host disease that is characterized by the lack of in vivo CTL and hyperproduction of Ig and autoantibodies that results in an SLE-like syndrome. One reason for the lack of donor antirecipient CTL after injection of DBA/2J donor cells is that B6D2F1 recipient cells functionally inactivate the donor DBA/2J CTL precursor cells by expressing veto activity. These B6D2F1 veto cells are radiosensitive, inhibited by anti-CD8 antibodies, found primarily in lymph nodes, and were further characterized by testing the response of these inhibitory cells to lymphokines. These studies indicate that IL-2 can potentiate the activity of the veto cells induced in vivo and veto cells with a similar phenotype can be generated by in vitro incubation of naive lymph node cells with IL-2. These cells have been designated as IL-2-activated veto cells or LAV cells. IL-2 did not increase inhibitory activity by increasing the number of CD8+ cells or the number of CD8 molecules on the LAV cell surface but by altering the activation state of the LAV cell. The inhibitory capabilities of antibodies binding various cell surface molecules indicated that CD2 and intercellular adhesion molecule-1 molecules in addition to CD8 molecules played a role in the function of LAV cells.     

Flow-distributed spikes for Schnakenberg kinetics

We study a system of reaction–diffusion–convection equations which combine a reaction–diffusion system with Schnakenberg kinetics and the convective flow equations. It serves as a simple model for flow-distributed pattern formation. We show how the choice of boundary conditions and the size of the flow influence the positions of the emerging spiky patterns and give conditions when they are shifted to the right or to the left. Further, we analyze the shape and prove the stability of the spikes. This paper is the first providing a rigorous analysis of spiky patterns for reaction-diffusion systems coupled with convective flow. The importance of these results for biological applications, in particular the formation of left–right asymmetry in the mouse, is indicated.     

Dendritic processing

Dendritic processing multiplies the computational power of a single neuron by enabling the processing of inputs in a spatio-temporally differentiated manner. Recently, the development of new and refined optical, electrophysiological and molecular-biological techniques has led to new insights into dendritic function and revealed an astonishing plethora of computational mechanisms.     

Dendritic morphogenesis

Neurons are polarized cells with an axon and a dendritic arbor extending from the soma. Although the molecular mechanisms underlying axon guidance are rapidly being elucidated, those that regulate the orientation, morphology, and elaboration of dendritic processes are largely unknown. Several recent papers address these issues, and propose a set of molecular strategies that control dendrite development. This review discusses these papers and what they reveal to us about how cell signaling orchestrates neuronal form and connectivity during development.     

The GABAB1b isoform mediates long-lasting inhibition of dendritic Ca2+ spikes in layer 5 somatosensory pyramidal neurons

The apical tuft of layer 5 pyramidal neurons is innervated by a large number of inhibitory inputs with unknown functions. Here, we studied the functional consequences and underlying molecular mechanisms of apical inhibition on dendritic spike activity. Extracellular stimulation of layer 1, during blockade of glutamatergic transmission, inhibited the dendritic Ca2+ spike for up to 400 ms. Activation of metabotropic GABAB receptors was responsible for a gradual and long-lasting inhibitory effect, whereas GABAA receptors mediated a short-lasting (approximately 150 ms) inhibition. Our results suggest that the mechanism underlying the GABAB inhibition of Ca2+ spikes involves direct blockade of dendritic Ca2+ channels. By using knockout mice for the two predominant GABAB1 isoforms, GABAB1a and GABAB1b, we showed that postsynaptic inhibition of Ca2+ spikes is mediated by GABAB1b, whereas presynaptic inhibition of GABA release is mediated by GABAB1a. We conclude that the molecular subtypes of GABAB receptors play strategically different physiological roles in neocortical neurons.