Dendritic integration in olfactory bulb granule cells upon simultaneous multispine activation: Low thresholds for nonlocal spiking activity

Abstract

The inhibitory axonless olfactory bulb granule cells form reciprocal dendrodendritic synapses with mitral and tufted cells via large spines, mediating recurrent and lateral inhibition. As a case in point for dendritic transmitter release, rat granule cell dendrites are highly excitable, featuring local Na + spine spikes and global Ca 2+-and Na +-spikes. To investigate the transition from local to global signaling, we performed holographic, simultaneous 2-photon uncaging of glutamate at up to 12 granule cell spines, along with whole-cell recording and dendritic 2-photon Ca 2+ imaging in acute juvenile rat brain slices. Coactivation of less than 10 reciprocal spines was sufficient to generate diverse regenerative signals that included regional dendritic Ca 2+-spikes and dendritic Na +-spikes (D-spikes). Global Na +-spikes could be triggered in one third of granule cells. Individual spines and dendritic segments sensed the respective signal transitions as increments in Ca 2+ entry. Dendritic integration as monitored by the somatic membrane potential was mostly linear until a threshold number of spines was activated, at which often D-spikes along with supralinear summation set in. As to the mechanisms supporting active integration, NMDA receptors (NMDARs) strongly contributed to all aspects of supralinearity, followed by dendritic voltage-gated Na +-and Ca 2+channels, whereas local Na + spine spikes, as well as morphological variables, barely mattered. Because of the low numbers of coactive spines required to trigger dendritic Ca 2+ signals and thus possibly lateral release of GABA onto mitral and tufted cells, we predict that thresholds for granule cell-mediated bulbar lateral inhibition are low. Moreover, D-spikes could provide a plausible substrate for granule cell-mediated gamma oscillations.

Presynaptic NMDARs cooperate with local spikes toward GABA release from the reciprocal olfactory bulb granule cell spine

“…The rather low P r_GABA observed here also implies that GC spines are likely to release with higher probabilities upon coincident non-local GC signaling (i.e. regional or global Ca 2+ or Na + spikes), due to substantially increased ∆Ca 2+ in the spine as observed previously ( Egger et al, 2005 ; Egger, 2008 ; Aghvami et al, 2019 ; Mueller and Egger, 2020 ). Therefore, we predict such coincident non-local activity to boost both recurrent and lateral inhibition.…”

Olfactory bulb granule cells: specialized to link coactive glomerular columns for percept generation and discrimination of odors

“…(1) The involved GCs have to be excited sufficiently to generate a non-local spike (i.e., a spike that invades a larger dendritic compartment and its spines) or global spike. Evidence for global GC spiking upon uniglomerular activation in vitro has been observed by several groups, including our own (e.g., Schoppa et al 1998;Egger 2008;Stroh et al 2012; Burton and Urban 2015); as described above, rather low numbers of coactivated spines on GC apical dendrites (< 10) are sufficient to elicit global spiking and even less to elicit non-local, dendritic spiking (Mueller and Egger 2020). If a given GC can be fired via the activation of the MTCs associated with a particular glomerular column, it belongs to this column.…”

“…To this end, we have established a holographic uncaging system that allows for simultaneous multi-site stimulation, thereby preventing the inactivation of voltage-dependent conductances expected during sequential uncaging (Go et al 2019). We find that even though GCs show a rather hyperpolarized membrane potential, a quite small number of coactivated spines on their apical dendrite is sufficient to trigger non-local, dendritic Ca 2+ and Na + spikes, and even global Na + spikes require no more than ~ 9 simultaneous apical inputs (Mueller and Egger 2020). Thus, the threshold for lateral inhibition is low.…”

A17 Amacrine Cells and Olfactory Granule Cells: Parallel Processors of Early Sensory Information

“…GC spines provide independent feedback inhibition (e.g., Isaacson and Strowbridge, 1998) in response to local unitary MTC input (Lage-Rupprecht et al, 2020), casting GCs, like A17s, as parallel processors. Accordingly, GC outputs are probably not activated solely by propagating dendritic action potentials, even though thresholds for such global signals are low (Lage-Rupprecht et al, 2020;Müller and Egger, 2020), although definitive experiments with paired MTC-GC recordings have remained elusive (Isaacson, 2001;Kato et al, 2013;Pressler and Strowbridge, 2017). These results suggest that GCs may be unable to inhibit MTCs in neighboring, quiescent glomeruli, a critical component of olfactory contrast enhancement, as observed in vivo (Fukunaga et al, 2014).…”

“…GCs employ distinct voltage-gated calcium (Ca v ) channel subtypes for different tasks: T-type and L-type channels mediate Ca 2+ influx into dendrites and spines (Egger et al, 2003(Egger et al, , 2005Midtgaard, 2003, 2005;Pressler and Strowbridge, 2019;Müller and Egger, 2020), but N/P/Q-type Ca v s (along with NMDA receptors, see below) provide the Ca 2+ required for synaptic release (Isaacson, 2001;Lage-Rupprecht et al, 2020). A17s, together with most non-spiking cells in the retinal circuitry (Pangrsic et al, 2018), express primarily L-type Ca v channels (Grimes et al, 2010).…”