Highlights d Mechanisms underlying rhythm generation in preBö tzinger complex are unknown d Rhythm emerges via spike synchronization of neurons in the rhythmogenic microcircuit d Excitation-inhibition balance within the microcircuit regulates synchrony d Reliable propagation of inspiratory command to motoneurons enhanced by synchrony

Key points• Active calcium signal propagation occurs when an initial calcium trigger elicits calcium release through endoplasmic reticulum (ER) receptors. A high concentration of the calcium trigger in thin-calibre dendrites would suppress release of calcium through hippocampal inositol trisphosphate receptors (InsP 3 Rs).• Could the high-density expression of A-type K + channels in thin-calibre dendrites be a mechanism for inhibiting this suppression, thereby restoring the utility of the ER as a substrate for active calcium propagation?• Quantitative analyses involving experimentally constrained models reveal a bell-shaped dependence of calcium released through InsP 3 Rs on the A-type K + channel density, during the propagation of a calcium wave.• A-type K + channels regulated the relative contribution of ER calcium to the induction of synaptic plasticity in the presence of model metabotropic glutamate receptors.• These results identify a novel form of interaction between active dendrites and the ER membrane and suggest that A-type K + channels are ideally placed for inhibiting the suppression of InsP 3 Rs in thin-calibre dendrites.Abstract The A-type potassium current has been implicated in the regulation of several physiological processes. Here, we explore a role for the A-type potassium current in regulating the release of calcium through inositol trisphosphate receptors (InsP 3 R) that reside on the endoplasmic reticulum (ER) of hippocampal pyramidal neurons. To do this, we constructed morphologically realistic, conductance-based models equipped with kinetic schemes that govern several calcium signalling modules and pathways, and constrained the distributions and properties of constitutive components by experimental measurements from these neurons. Employing these models, we establish a bell-shaped dependence of calcium release through InsP 3 Rs on the density of A-type potassium channels, during the propagation of an intraneuronal calcium wave initiated through established protocols. Exploring the sensitivities of calcium wave initiation and propagation to several underlying parameters, we found that ER calcium release critically depends on dendritic diameter and that wave initiation occurred at branch points as a consequence of a high surface area to volume ratio of oblique dendrites. Furthermore, analogous to the role of A-type potassium channels in regulating spike latency, we found that an increase in the density of A-type potassium channels led to increases in the latency and the temporal spread of a propagating calcium wave. Next, we incorporated kinetic models for the metabotropic glutamate receptor (mGluR) signalling components and a calcium-controlled plasticity rule into our model and demonstrate that the presence of mGluRs induced a leftward shift in a Bienenstock-Cooper-Munro-like synaptic plasticity profile. Finally, we show that the A-type potassium current could regulate the relative contribution of ER calcium to synaptic plasticity induced either through 900 pulses of various stimulus frequ...

An important consequence of gliotransmission, a signaling mechanism that involves glial release of active transmitter molecules, is its manifestation as N-methyl-D-aspartate receptor (NMDAR)-dependent slow inward currents in neurons. However, the intraneuronal spatial dynamics of these events or the role of active dendrites in regulating their amplitude and spatial spread have remained unexplored. Here, we used somatic and/or dendritic recordings from rat hippocampal pyramidal neurons and demonstrate that a majority of NMDAR-dependent spontaneous slow excitatory potentials (SEP) originate at dendritic locations and are significantly attenuated through their propagation across the neuronal arbor. We substantiated the astrocytic origin of SEPs through paired neuron-astrocyte recordings, where we found that specific infusion of inositol trisphosphate (InsP 3 ) into either distal or proximal astrocytes enhanced the amplitude and frequency of neuronal SEPs. Importantly, SEPs recorded after InsP 3 infusion into distal astrocytes exhibited significantly slower kinetics compared with those recorded after proximal infusion. Furthermore, using neuron-specific infusion of pharmacological agents and morphologically realistic conductance-based computational models, we demonstrate that dendritically expressed hyperpolarization-activated cyclic-nucleotide-gated (HCN) and transient potassium channels play critical roles in regulating the strength, kinetics, and compartmentalization of neuronal SEPs. Finally, through the application of subtypespecific receptor blockers during paired neuron-astrocyte recordings, we provide evidence that GluN2B-and GluN2D-containing NMDARs predominantly mediate perisomatic and dendritic SEPs, respectively. Our results unveil an important role for active dendrites in regulating the impact of gliotransmission on neurons and suggest astrocytes as a source of dendritic plateau potentials that have been implicated in localized plasticity and place cell formation.neuron-astrocyte interaction | NMDA receptors | HCN channels | transient potassium channels | plateau potentials G liotransmission, a signaling mechanism that involves glial release of active transmitter molecules, has been implicated in the regulation of several neurophysiological processes that include synaptogenesis, synaptic transmission and plasticity, neuronal excitability, and synchrony (1-3). An important consequence of gliotransmission is its manifestation as slow inward currents (SIC), events that are mediated by neuronal extrasynaptic N-methyl-D-aspartate receptors (NMDAR) and are concomitant to astrocytic calcium elevations (3-8). Although these well-studied events have provided us with important insights into tripartite neuron-astrocyte interactions (1-9), recordings of such SICs have focused predominantly on the soma despite the dendritic localization of a majority of synapses (10). Research over the past two decades has clearly established that dendritic processing critically contributes to neuronal physiology and is best assesse...

Breathing is a vital rhythmic motor behavior with a surprisingly broad influence on the brain and body. The apparent simplicity of breathing belies a complex neural control system, the breathing central pattern generator (bCPG), that exhibits diverse operational modes to regulate gas exchange and coordinate breathing with an array of behaviors. In this review, we focus on selected advances in our understanding of the bCPG. At the core of the bCPG is the preBötzinger complex (preBötC), which drives inspiratory rhythm via an unexpectedly sophisticated emergent mechanism. Synchronization dynamics underlying preBötC rhythmogenesis imbue the system with robustness and lability. These dynamics are modulated by inputs from throughout the brain and generate rhythmic, patterned activity that is widely distributed. The connectivity and an emerging literature support a link between breathing, emotion, and cognition that is becoming experimentally tractable. These advances bring great potential for elucidating function and dysfunction in breathing and other mammalian neural circuits. Expected final online publication date for the Annual Review of Neuroscience, Volume 45 is July 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Glial cells and neuronal dendrites were historically assumed to be passive structures that play only supportive physiological roles, with no active contribution to information processing in the central nervous system. Research spanning the past few decades has clearly established this assumption to be far from physiological realities. Whereas the discovery of active channel conductances and their localized plasticity was the turning point for dendritic structures, the demonstration that glial cells release transmitter molecules and communicate across the neuroglia syncytium through calcium wave propagation constituted path-breaking discoveries for glial cell physiology. An additional commonality between these two structures is the ability of calcium stores within their endoplasmic reticulum (ER) to support active propagation of calcium waves, which play crucial roles in the spatiotemporal integration of information within and across cells. Although there have been several demonstrations of regulatory roles of glial cells and dendritic structures in achieving common physiological goals such as information propagation and adaptability through plasticity, studies assessing physiological interactions between these two active structures have been few and far. This lacuna is especially striking given the strong connectivity that is known to exist between these two structures through several complex and tightly intercoupled mechanisms that also recruit their respective ER structures. In this review, we present brief overviews of the parallel literatures on active dendrites and active glial physiology and make a strong case for future studies to directly assess the strong interactions between these two structures in regulating physiology and pathophysiology of the brain.