Anatomical and Functional Connectivity at the Dendrodendritic Reciprocal Mitral Cell–Granule Cell Synapse: Impact on Recurrent and Lateral Inhibition

Abstract

In the vertebrate olfactory bulb, reciprocal dendrodendritic interactions between its principal neurons, the mitral and tufted cells, and inhibitory interneurons in the external plexiform layer mediate both recurrent and lateral inhibition, with the most numerous of these interneurons being granule cells. Here, we used recently established anatomical parameters and functional data on unitary synaptic transmission to simulate the strength of recurrent inhibition of mitral cells specifically from the reciprocal spines of rat olfactory bulb granule cells in a quantitative manner. Our functional data allowed us to derive a unitary synaptic conductance on the order of 0.2 nS. The simulations predicted that somatic voltage deflections by even proximal individual granule cell inputs are below the detection threshold and that attenuation with distance is roughly linear, with a passive length constant of 650 μm. However, since recurrent inhibition in the wake of a mitral cell action potential will originate from hundreds of reciprocal spines, the summated recurrent IPSP will be much larger, even though there will be substantial mutual shunting across the many inputs. Next, we updated and refined a preexisting model of connectivity within the entire rat olfactory bulb, first between pairs of mitral and granule cells, to estimate the likelihood and impact of recurrent inhibition depending on the distance between cells. Moreover, to characterize the substrate of lateral inhibition, we estimated the connectivity via granule cells between any two mitral cells or all the mitral cells that belong to a functional glomerular ensemble (i.e., which receive their input from the same glomerulus), again as a function of the distance between mitral cells and/or entire glomerular mitral cell ensembles. Our results predict the extent of the three regimes of anatomical connectivity between glomerular ensembles: high connectivity within a glomerular ensemble and across the first four rings of adjacent glomeruli, substantial connectivity to up to eleven glomeruli away, and negligible connectivity beyond. Finally, in a first attempt to estimate the functional strength of granule-cell mediated lateral inhibition, we combined this anatomical estimate with our above simulation results on attenuation with distance, resulting in slightly narrowed regimes of a functional impact compared to the anatomical connectivity.

Fast-spiking interneuron detonation drives high-fidelity inhibition in the olfactory bulb

“…By avoiding profuse basket innervation of individual MTC somata, FSI dendrites can likely reciprocally communicate with a larger ensemble of MTCs. While lacking canonical basket-like structure, perisomatic inhibition of MTCs by FSIs nevertheless proved surprisingly strong, hyperpolarizing MTCs by 0.46±0.45 mV from resting potentials of -53.0±3.3 mV (n=8), comparable to unitary basket cell hyperpolarization of hippocampal and neocortical pyramidal cells by 0.45 and 1.2 mV, respectively, from resting potentials of -55 to -60 mV in adult rats (Buhl et al, 1995;Thomson et al, 1996) and far exceeding the predicted unitary GC-to-MTC IPSP amplitude of 0.01-0.03 mV (Aghvami et al, 2022). FSIs in the OB may thus achieve comparable function as cortical basket cells through strikingly distinct synaptic architecture.…”

“…To investigate this, we hyperpolarized FSIs in reciprocally-connected MTC–FSI pairs through negative current injection on interleaved trials, blocking detonation and revealing massive underlying uEPSPs (Figure 3D), and then examined the difference in mean MTC currents across detonation vs. uEPSP trials. Of note, each MTC can reciprocally interact with up to an estimated 10 4 GCs (Egger and Urban, 2006; Aghvami et al, 2022), suggesting that resolving the recurrent feedback mediated by any one interneuron through somatic recording may prove exceedingly difficult unless such inhibition is particularly strong and reliable. Strikingly, our subtraction procedure indeed isolated clear recurrent IPSCs strongly timelocked to FSI detonation latencies (Figure 3E).…”

“…Our results thus point toward a positive feedback loop between MTC synchronization and fast lateral inhibition as a potential circuit operation supported by FSIs. Understanding the net contribution of FSIs to sensory processing in the OB will further require assessing the strength of FSI-to-MTC inhibition relative to total MTC inhibition following sensory activation of the OB circuit, particularly given that each MTC receives inhibitory input from an estimated 10 4 GCs (Egger and Urban, 2006;Aghvami et al, 2022). In our final experiment, we therefore combined MTC-FSI pair recordings with optogenetic activation of olfactory sensory neuron terminals to assess the contribution of single FSIs to total network-driven MTC lateral inhibition.…”

The spiking output of the mouse olfactory bulb encodes large-scale temporal features of natural odor environments

“…This is a result of the dendrodendritic connections MCs form with granules cells. These connections also result in a greater amount of surround inhibition for MCs (Geramita et al, 2016), exerted upon their millimeter-long lateral dendrites (Aghvami et al, 2022). This could possibly provide individual MCs with informative lateral inhibition from other MCs across the bulb.…”

Shared and divergent principles of synaptic transmission between cortical excitatory neurons in rodent and human brain

“…The basic blueprint of the synapse typically includes the neurotransmitter release machinery of the presynaptic axon and the associated receptor complex on the postsynaptic dendrite. However, this simplified scheme is easily extended to a spectrum of synapse types, including (i) axo-axonic synapses ( Somogyi, 1977 ; Gonchar et al, 2002 ; Schneider-Mizell et al, 2021 ), (ii) axo-somatic synapses ( Borst and Soria van Hoeve, 2012 ; Kubota et al, 2016 ), (iii) dendro-dendritic synapses [( Woolf et al, 1991 ; Aghvami et al, 2022 )], or (iii) the tripartite synapse with juxta-posed astrocytes [( Araque et al, 1999 ; Liu et al, 2023 )]. Furthermore, a single postsynaptic spine can be occupied by multiple presynaptic terminals and contact points are found between axonal bouton and postsynaptic spine neck or dendritic shaft ( Cano-Astorga et al, 2021 ).…”