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• W2058616589 abstract "Pyramidal cell dendrites are able to produce a variety of active calcium signals in brain slices. In this issue of Neuron, Grienberger et al., 2014Grienberger C. Chen X. Konnerth A. Neuron. 2014; 81 (this issue): 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar investigate dendritic function in the hippocampus of live mice. Pyramidal cell dendrites are able to produce a variety of active calcium signals in brain slices. In this issue of Neuron, Grienberger et al., 2014Grienberger C. Chen X. Konnerth A. Neuron. 2014; 81 (this issue): 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar investigate dendritic function in the hippocampus of live mice. Fluorescent Ca2+ indicators have forever changed our view of how neurons work. Rather than passively propagating synaptic currents to the soma, a rich repertoire of active events has been discovered in pyramidal cell dendrites, including Na+ spikes, Ca2+ spikes, NMDA spikes, and wave-like Ca2+ release events from intracellular Ca2+ stores (Schiller et al., 2000Schiller J. Major G. Koester H.J. Schiller Y. Nature. 2000; 404: 285-289Crossref PubMed Scopus (484) Google Scholar, Nakamura et al., 1999Nakamura T. Barbara J.G. Nakamura K. Ross W.N. Neuron. 1999; 24: 727-737Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). In the past, most calcium imaging studies have been conducted in brain slices, and some forms of dendritic calcium signaling can be observed only under quite specific stimulation conditions. Clearly, the spatial distribution of excitatory inputs, the degree and timing of inhibition, and the presence or absence of modulatory inputs all affect the frequency and extent of dendritic calcium signals. In this issue of Neuron, Grienberger et al., 2014Grienberger C. Chen X. Konnerth A. Neuron. 2014; 81 (this issue): 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar investigate dendritic Ca2+ signals in hippocampal pyramidal cells of live mice. As even two-photon microscopy cannot penetrate brain tissue deeper than about 1 mm, the authors removed a small portion of neocortex to gain optical access to the hippocampus. Individual pyramidal cells in CA1 were loaded with the high-affinity calcium dye OGB1 through a patch pipette. Two types of calcium signals occurred spontaneously in anesthetized mice, reflecting ongoing physiological activity: very small and localized calcium “blips” were associated with small somatic depolarizations and probably reflect the activity of individual excitatory synapses. The other type of event was very large, flooding all basal dendrites simultaneously with Ca2+ (Figure 1A). These generalized calcium events were associated with complex spike bursts, a type of high-frequency discharge that is known to occur in CA1 pyramidal cells during behavior (Harris et al., 2001Harris K.D. Hirase H. Leinekugel X. Henze D.A. Buzsáki G. Neuron. 2001; 32: 141-149Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar). Grienberger et al., 2014Grienberger C. Chen X. Konnerth A. Neuron. 2014; 81 (this issue): 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar used specific intracellular blockers to show that activation of postsynaptic NMDA receptors and voltage-dependent Ca2+ channels is essential for the generation of complex spike bursts and pandendritic calcium spikes. Interestingly, the function of this dendritic amplifier was highly dependent on the cell’s membrane potential: at potentials below −60 mV, no complex spike bursts were generated. In CA1 neurons that did not produce complex spike bursts spontaneously, a small constant current injection was sufficient to activate dendritic amplification and burst firing. What is the physiological function of active dendritic amplification in the hippocampus? CA1 is famous for its “place cells,” neurons that fire brief bursts of action potentials when the animal is crossing a specific position in its cage (O’Keefe and Dostrovsky, 1971O’Keefe J. Dostrovsky J. Brain Res. 1971; 34: 171-175Crossref PubMed Scopus (3797) Google Scholar). This position-sensitive firing, however, is seen only in a subset of CA1 pyramidal cells. Recently, it has been shown that a small sustained current injection can convert any CA1 cell into a place cell with its characteristic spatial tuning (Lee et al., 2012Lee D. Lin B.-J. Lee A.K. Science. 2012; 337: 849-853Crossref PubMed Scopus (170) Google Scholar) (Figure 1B). Curiously, not even subthreshold depolarizations could be detected in the “quiescent” place cells in the absence of current injection. This was puzzling, as the observed spatial specificity must arise from appropriately tuned synaptic inputs that should leave a trace in the form of subthreshold excitatory postsynaptic potentials. Considering the new data from Grienberger et al., 2014Grienberger C. Chen X. Konnerth A. Neuron. 2014; 81 (this issue): 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, it seems that in the absence of dendritic amplification, spatially tuned synaptic inputs on distal dendrites completely lose their oomph on the way to the soma, preventing efficient summation and action potential generation. The cellular mechanisms investigated by Grienberger et al., 2014Grienberger C. Chen X. Konnerth A. Neuron. 2014; 81 (this issue): 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar might thus be responsible for the emergence of place cells in CA1. Bursts of action potentials, as opposed to single spikes, are thought to signal events of special importance to the animal. NMDA receptors, as they integrate glutamate at individual synapses over 50–100 ms, can be thought of as specialized “burst sensors” in the synapse. In addition, their activation leads to prolonged depolarization of the postsynaptic neuron, which is essential for burst firing. Thus, NMDA receptors are poised to propagate bursts through the cortical network (Polsky et al., 2009Polsky A. Mel B. Schiller J. J. Neurosci. 2009; 29: 11891-11903Crossref PubMed Scopus (100) Google Scholar). This role was postulated based on slice experiments and has now been nicely confirmed by patch-clamp recording in vivo (Grienberger et al., 2014Grienberger C. Chen X. Konnerth A. Neuron. 2014; 81 (this issue): 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). In addition to acting as a voltage-dependent amplifier, the NMDA receptor is also distinguished by its very high permeability for Ca2+. The massive dendritic Ca2+ transients generated during complex burst firing could act as positive feedback signals, strengthening and stabilizing the synapses that causally contributed to burst initiation. Indeed, complex spike bursts enable the induction of LTP during 5 Hz stimulation, a frequency that is prominent in the hippocampus during active behavior and REM sleep (Thomas et al., 1998Thomas M.J. Watabe A.M. Moody T.D. Makhinson M. O’Dell T.J. J. Neurosci. 1998; 18: 7118-7126PubMed Google Scholar). In this context, it is interesting to note that in CA1 pyramidal cells, spike-timing-dependent plasticity protocols also require three postsynaptic spikes for reliable potentiation (Holbro et al., 2010Holbro N. Grunditz A. Wiegert J.S. Oertner T.G. Proc. Natl. Acad. Sci. USA. 2010; 107: 15975-15980Crossref PubMed Scopus (29) Google Scholar, Frey et al., 2009Frey M.C. Sprengel R. Nevian T. J. Neurosci. 2009; 29: 5587-5596Crossref PubMed Scopus (30) Google Scholar). Pairing of synaptic input with a single spike has little effect on synaptic strength in these cells. Thus, it is possible that the generalized calcium transients observed by Grienberger et al., 2014Grienberger C. Chen X. Konnerth A. Neuron. 2014; 81 (this issue): 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar reflect the adjustment of synaptic weights on a cell-wide scale. While NMDA spikes alone are apparently not sufficient to induce LTP (Gordon et al., 2006Gordon U. Polsky A. Schiller J. J. Neurosci. 2006; 26: 12717-12726Crossref PubMed Scopus (131) Google Scholar), complex spike busts might, and it will be important to investigate the timing rules of such burst-timing-dependent plasticity. A very interesting aspect of the new study is what was not observed: Grienberger et al., 2014Grienberger C. Chen X. Konnerth A. Neuron. 2014; 81 (this issue): 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar do not report any regenerative Ca2+ signals restricted to individual branches. The discovery of such local NMDA spikes in neocortical pyramidal cells generated a lot of interest as they could reflect specific dendritic computations performed by clusters of coactive synapses (Major et al., 2008Major G. Polsky A. Denk W. Schiller J. Tank D.W. J. Neurophysiol. 2008; 99: 2584-2601Crossref PubMed Scopus (136) Google Scholar). A recent in vivo imaging study on layer 2/3 pyramidal neurons provided clear evidence that local NMDA spikes occur in the apical tuft of these smaller neurons, most frequently after sensory stimulation (Palmer et al., 2014Palmer L.M. Shai A.S. Reeve J.E. Anderson H.L. Paulsen O. Larkum M.E. Nat. Neurosci. 2014; 17: 383-390Crossref PubMed Scopus (170) Google Scholar). In layer 2/3 neurons, local NMDA spikes strongly increase the probability of action potential generation after sensory input but are not associated with complex spike bursts. In CA1 pyramidal neurons, in contrast, even intense and focal stimulation triggers an NMDA spike only in the wake of a dendritic Na+ spike (Ariav et al., 2003Ariav G. Polsky A. Schiller J. J. Neurosci. 2003; 23: 7750-7758PubMed Google Scholar). In the intact hippocampus, coactive inputs might be widely distributed across the dendritic tree. Thus, both cellular properties of CA1 pyramidal cells and the sparse, distributed connectivity of the hippocampus could explain why local NMDA spikes were not observed in the basal dendrites. In addition, potential local NMDA spikes could be immediately masked by the generation of a global Ca2+ spike. Indeed, Grienberger et al., 2014Grienberger C. Chen X. Konnerth A. Neuron. 2014; 81 (this issue): 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar report a strong dependence of global Ca2+ events on voltage-gated Ca2+ channels, while these channels contribute little to NMDA spikes in neocortical pyramidal cells (Major et al., 2008Major G. Polsky A. Denk W. Schiller J. Tank D.W. J. Neurophysiol. 2008; 99: 2584-2601Crossref PubMed Scopus (136) Google Scholar). It is also possible that NMDA spikes are generated in oblique or distal apical dendrites of CA1 cells, regions that are still out of reach for functional imaging in vivo (Figure 1A). Or they might occur during specific behavioral states, but not under anesthesia. The question of local dendritic amplification will certainly remain a subject of intense and technology-driven research. For example, NMDA trigger zones of Ca2+ spikes might have been obscured due to saturation of OGB-1, and the latest generation of genetically encoded Ca2+ indicators could help reveal differences between individual dendritic branches during complex spike bursts. In summary, NMDA receptors act as gated coincidence detectors: dendritic amplification and telltale Ca2+ transients can be switched “on” or “off” by small changes in membrane potential, which in turn is set by the integration of all excitatory and inhibitory inputs. In CA1, integrated synaptic activity seems to select a subset of pyramidal cells to function as place cells (Lee et al., 2012Lee D. Lin B.-J. Lee A.K. Science. 2012; 337: 849-853Crossref PubMed Scopus (170) Google Scholar), which could explain why the stability of place fields is strongly dependent on task requirements and attention (Kentros et al., 2004Kentros C.G. Agnihotri N.T. Streater S. Hawkins R.D. Kandel E.R. Neuron. 2004; 42: 283-295Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). As a parent keeping control of their rowdy flock, CA1 pyramidal cells keep dendritic amplification under strict somatic voltage control (Grienberger et al., 2014Grienberger C. Chen X. Konnerth A. Neuron. 2014; 81 (this issue): 1274-1281Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). Neocortical pyramidal cells, on the other hand, seem to support a much more diverse repertoire of local and global signaling modes (Major et al., 2008Major G. Polsky A. Denk W. Schiller J. Tank D.W. J. Neurophysiol. 2008; 99: 2584-2601Crossref PubMed Scopus (136) Google Scholar). While it is reassuring that most phenomena that were originally discovered in slice preparations can now be observed in the intact animal, one has to keep in mind: not all pyramidal cells are created equal. NMDA Receptor-Dependent Multidendrite Ca2+ Spikes Required for Hippocampal Burst Firing In VivoGrienberger et al.NeuronFebruary 20, 2014In BriefUsing two-photon functional imaging of dendrites combined with whole-cell recordings in the mouse hippocampus in vivo, Grienberger et al. identify multidendrite NMDA receptor-dependent Ca2+ spikes as critical determinants of complex spike burst activity in CA1 pyramidal neurons. Full-Text PDF Open Archive" @default.
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• W2058616589 title "Active Dendrites under Parental Supervision" @default.
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