NMDA receptor–BK channel coupling regulates synaptic plasticity in the barrel cortex

Abstract

Postsynaptic N-methyl-D-aspartate receptors (NMDARs) are crucial mediators of synaptic plasticity due to their ability to act as coincidence detectors of presynaptic and postsynaptic neuronal activity. However, NMDARs exist within the molecular context of a variety of postsynaptic signaling proteins, which can fine-tune their function. Here, we describe a form of NMDAR suppression by large-conductance Ca2+- and voltage-gated K+ (BK) channels in the basal dendrites of a subset of barrel cortex layer 5 pyramidal neurons. We show that NMDAR activation increases intracellular Ca2+ in the vicinity of BK channels, thus activating K+ efflux and strong negative feedback inhibition. We further show that neurons exhibiting such NMDAR–BK coupling serve as high-pass filters for incoming synaptic inputs, precluding the induction of spike timing–dependent plasticity. Together, these data suggest that NMDAR-localized BK channels regulate synaptic integration and provide input-specific synaptic diversity to a thalamocortical circuit.

Structural and Functional Coupling of Calcium-Activated BK Channels and Calcium-Permeable Channels Within Nanodomain Signaling Complexes

“…EGTA-insensitive coupling of BK channels with NMDARs was also recently observed in a subset of barrel cortex layer 5 pyramidal neurons (BC-L5PNs) but when NMDA was applied toward basal dendrites instead of soma (Gomez et al, 2021). In a heterologous expression system of HEK293 cells, similar results of BK-NMDAR (GluN1/GluN2A) functional coupling were revealed by whole cell voltage-clamp recording (Zhang et al, 2018).…”

“…Postsynaptic BK-NMDAR coupling was also recently reported to occur in the basal dendrites of approximately 40% of BC-L5PNs (Gomez et al, 2021). The application of NMDA toward basal dendrites led to large NMDAR inward and BK channel outward currents recorded in soma, supporting dendritic locations of BK-NMDAR coupling (Gomez et al, 2021).…”

“…With in situ PLA, BKα and GluN1 were found to be colocalized in both the heterologous expression system and, broadly, in different regions of mouse hippocampus (Zhang et al, 2018). Consistent with the sole requirement of GluN1 for protein complex formation with BK channels (Zhang et al, 2018), PLA with HEK293 cells co-expressing BK channels with GluN1/GluN2A or GluN1/GluN2B showed no preference in BK channels' proximity to these 2 types of NMDARs (Gomez et al, 2021). In the dentate gyrus, PLA signals of the BKα-GluN1 complexes were most abundant in the molecular layer region (Zhang et al, 2018), which is consistent with the predominant dendritic distribution of NMDARs.…”

“…The colocalization of BK and NMDARs was probed with an in situ PLA (Zhang et al, 2018;Gomez et al, 2021). PLA displays point-like staining signals only when the 2 epitopes on the interacting proteins for primary antibodies are in proximity (<40 nm) (Soderberg et al, 2006), making PLA a suitable assay for the detection of protein colocalization within the nanodomain.…”

“…In excised inside-out membrane patches of HEK293 cells, BK channel openings at the single channel level were observed upon NMDAR activation using flash photolysis of caged NMDA (Zhang et al, 2018). In HEK293 cells, activation of NMDARs formed by GluN1/GluN2A or GluN1/GluN2B both resulted in large shifts in the apparent voltage dependence of BK channel activation (Gomez et al, 2021).…”