Dendritic branch structure compartmentalizes voltage-dependent calcium influx in cortical layer 2/3 pyramidal cells

Abstract

Back-propagating action potentials (bAPs) regulate synaptic plasticity by evoking voltage-dependent calcium influx throughout dendrites. Attenuation of bAP amplitude in distal dendritic compartments alters plasticity in a location-specific manner by reducing bAP-dependent calcium influx. However, it is not known if neurons exhibit branch-specific variability in bAP-dependent calcium signals, independent of distance-dependent attenuation. Here, we reveal that bAPs fail to evoke calcium influx through voltage-gated calcium channels (VGCCs) in a specific population of dendritic branches in mouse cortical layer 2/3 pyramidal cells, despite evoking substantial VGCC-mediated calcium influx in sister branches. These branches contain VGCCs and successfully propagate bAPs in the absence of synaptic input; nevertheless, they fail to exhibit bAP-evoked calcium influx due to a branch-specific reduction in bAP amplitude. We demonstrate that these branches have more elaborate branch structure compared to sister branches, which causes a local reduction in electrotonic impedance and bAP amplitude. Finally, we show that bAPs still amplify synaptically-mediated calcium influx in these branches because of differences in the voltage-dependence and kinetics of VGCCs and NMDA-type glutamate receptors. Branch-specific compartmentalization of bAP-dependent calcium signals may provide a mechanism for neurons to diversify synaptic tuning across the dendritic tree.

Asymmetric voltage attenuation in dendrites can enable hierarchical heterosynaptic plasticity

“…Further work can explore diverse neuronal types with different dendritic morphologies to examine whether the branching structure of different neurons may lend themselves to different kinds of plasticity computations. For example, the elaborate fractal branching structure of Purkinje neurons may lend those neurons to be optimized for segregated hierarchical units, while neurons with long, branching dendrites (such as apical dendrites of L2/3 cells) may exhibit more attenuation in the proximal-distal direction and thus behave less hierarchically, as descendant branches themselves can act as electrical sinks relative to the parent branch if there is sufficient surface area in the descendant branches [57].…”

“…For example, the elaborate fractal branching structure of Purkinje neurons may lend those neurons to be optimized for segregated hierarchical units (see (Liu et al, 2016;Piochon et al, 2007Piochon et al, , 2010 regarding the presence of NMDARs in Purkinje neurons and their influence on plasticity). Conversely, neurons with sufficiently long, branching dendrites (such as apical dendrites of L2/3 cells) may exhibit more attenuation in the proximal-to-distal direction and thus behave less hierarchically, as sufficiently long distal branches themselves can act as electrical sinks relative to the parent branch (Landau et al, 2022).…”

Synaptic NMDA receptor activity at resting membrane potentials

“…Figure 5D shows this same spine before (black traces) and after NBQX application (orange traces). NBQX decreased the EPSP size and reduced, but did not eliminate, the Ca 2+ influx into the spine, similar to uncaging-evoked responses in L2/3 dendritic spines (Landau et al, 2022), as well as stimulated responses in L4 dendritic spines (Nevian and Sakmann, 2004). Figure 5E shows a summary of eight experiments in which NBQX was added.…”

“…This observation shows that, rather than being an all-or-none switch depending on temporal coincidence of other depolarizing factors, NMDARs alone can contribute to synaptic function even in the case of isolated synaptic events. NMDAR-dependent Ca 2+ influx at subthreshold voltages has been previously observed in dendritic spines after local stimulation in CA1 neurons ( Sabatini et al, 2002 ) and cortical L2/3 neurons ( Nevian and Sakmann, 2006 ), as well as L2/3 dendritic spines in response to focal two-photon glutamate uncaging ( Landau et al, 2022 ).…”

“…Coincidence detection is particularly important for synaptic plasticity signaling in cortical L2/3 neurons, where back-propagating action potentials depolarize the dendritic membrane, leading to a large Ca 2+ influx in synapses with glutamate-bound NMDARs ( Nevian and Sakmann, 2006 ). Many postsynaptic factors contribute to this signaling mechanism, including the ability of the dendrites to support action potential back-propagation ( Nevian and Sakmann, 2004 ) and the local dendritic morphology ( Landau et al, 2022 ).…”