Selective activation of BK channels in small‐headed dendritic spines suppresses excitatory postsynaptic potentials

Abstract

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Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X Syndrome

“…Whole-cell patch clamp recordings in current-clamp were performed to measure the uncaging (u)-evoked excitatory postsynaptic potentials (uEPSP) at the soma. This technique allows for the precise activation of individual dendritic spines with responses that are similar to those from physiological activation of single synapses (Matsuzaki et al, 2001; Araya et al, 2006a; Araya et al, 2006b; Fino et al, 2009; Araya et al, 2013; Araya, 2014; Araya et al, 2014; Mitchell et al, 2019; Tazerart et al, 2020; Tazerart et al, 2022). As shown previously (Araya et al, 2006a), subthreshold synaptic inputs onto spines in the basal dendrites of WT L5 pyramidal neurons integrate linearly (Fig.…”

“…We next sought to identify the mechanism for this sublinear integration of spine activation in the basal dendrites of Fmr1 -KO L5 pyramidal neurons. Large conductance calcium-activated potassium (BK) channels are homogeneously distributed along the dendritic tree of L5 pyramidal neurons and are believed to play an important role in synaptic transmission and integration (Bock and Stuart, 2016; Tazerart et al, 2022). BK channels are high-conductance K + channel formed by a tetramer of α subunits.…”

“…Neck and spine head axial resistances were set to 500 and 150 MΩ respectively based on published values (O’Donnell et al, 2011; Harnett et al, 2012). High voltage-dependent Ca 2+ channels (HVA, https://senselab.med.yale.edu/modeldb/ShowModel?model=135787&file=/ShuEtAl20062007/ca.mod#tabs-2), Ca 2+ buffering/removal mechanisms (resting concentration of 1nM (Destexhe et al, 1993)), Nav1.6 sodium channels (3 S/cm 2 ; (Mercer et al, 2007)) and BK channels (14 S/cm 2 ) (Jaffe et al, 2011; Tazerart et al, 2022) were inserted in the spine heads. In one set of simulations, we incorporated the activation/deactivation parameters and kinetics of the α-subunit of BK channels, while in another set of simulations we used those obtained when the β4 subunit is bound to BK channels (Jaffe et al, 2011).…”

“…Briefly, a morphologically realistic L5 pyramidal neuron was built (adapted from Nevian et al, 2007;Tazerart et al, 2022) where two spines were simulated with neck lengths of 1µm and head volumes of 0.18 µm 3 , which matched the morphology of spines probed in our 2P experiments (Fig. 4a).…”

“…We reasoned that these integration impairments are due to spine channelopathies (Deng and Klyachko, 2021). Previous work has revealed that FMRP interacts with the β4 regulatory subunit of large-conductance voltage- and calcium-activated potassium (BK) channels (Deng et al, 2013), which are localized to dendritic spines where they play a role contributing to synaptic efficacy in L5 pyramidal neurons (Tazerart et al, 2022). Thus, in WT mice, FMRP can sequester the β4 subunit, as has been shown in the hippocampal pyramidal neurons (Deng et al, 2013), and prevent it from interacting with BK channels, whereas in Fmr1 -KO animals, an increased binding of BK channels and its β4 subunit would occur.…”