Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons

Abstract

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...

Heterogeneities in intrinsic excitability and frequency-dependent response properties of granule cells across the blades of the rat dentate gyrus

“…All experiments reported in this study were performed in strict adherence to the protocols cleared by the Institute Animal Ethics Committee (IAEC) of the Indian Institute of Science, Bangalore. Experimental procedures were similar to previously established protocols (Ashhad et al 2015; Ashhad and Narayanan 2016; Das and Narayanan 2017; Narayanan et al 2010; Narayanan and Johnston 2008; 2007; Rathour et al 2016) and are detailed below.…”

“…We characterized DG granule neurons using several electrophysiological measurements obtained through pulse-current and frequency-dependent current injections (Ashhad et al 2015; Ashhad and Narayanan 2016; Das and Narayanan 2017; Malik et al 2016; Mishra and Narayanan 2019; Narayanan et al 2010; Narayanan and Johnston 2008; 2007; Rathour et al 2016). Input resistance ( R in ) was measured as the slope of a linear fit to the steady-state V-I plot obtained by injecting subthreshold current pulses of amplitudes spanning –50 to +50 pA, in steps of 10 pA (Fig.…”

Degeneracy in hippocampal physiology and plasticity

“…The specific combination of changes that are recruited to mediate plasticity for a chosen protocol or for a given behavioral task would then be state‐dependent, critically reliant on the specific calcium sources (Section 3.3) and signaling cascades (Section 3.4) that were recruited in response to the induction protocol or a behavioral task. In addition to these neuronal components, glial cells, through several mechanisms including gliotransmission or transmitter reuptake and recycling mechanisms, have also been shown to play a critical role in synaptic plasticity (Araque et al, ; Ashhad & Narayanan, ; Ashhad & Narayanan, ; Halassa et al, ; Haydon & Carmignoto, ; Henneberger, Papouin, Oliet, & Rusakov, ; Pannasch & Rouach, ; Perea & Araque, ; Perea et al, ; Zorec et al, ), thereby adding another layer of parameters and another set of interactional complexity to the mechanistic basis for synaptic plasticity.…”

Spatially dispersed synapses yield sharply-tuned place cell responses through dendritic spike initiation

“…Second, absent in our model are several membrane and subcellular components, such as calcium stores on the endoplasmic reticulum, metabotropic receptors for different neurotrasmitters and neuromodulators, other channels such as the calcium-activated potassium, G-protein coupled and store-operated calcium, and well-established cross interactions among those components and channels/receptors included in our model (Ashhad and Narayanan, 2013;Grienberger et al, 2015). Third, activation of synapses carrying place field information could lead to gliotransmision or release of retrograde messengers from the pyramidal neuron that could affect the dendritic and network integration processes (Regehr et al, 2009;Araque et al, 2014;Ashhad and Narayanan, 2016). These limitations and missing components make a critical case for their incorporation into future models with different synaptic (including inhibitory and neuromodulatory synapses) localization profiles, including their short-term synaptic dynamics (Regehr, 2012).…”