mGluR5‐dependent modulation of dendritic excitability in CA1 pyramidal neurons mediated by enhancement of persistent Na⁺ currents

Abstract

Dendritic Na channels in pyramidal neurons are known to amplify synaptic signals, thereby facilitating action potential (AP) generation. However, the mechanisms that modulate dendritic Na channels have remained largely uncharacterized. Here, we report a new form of short-term plasticity in which proximal excitatory synaptic inputs to hippocampal CA1 pyramidal neurons transiently elevate dendritic excitability. High-frequency stimulations (HFS) to the Schaffer collateral (SC) pathway activate mGluR5-dependent Ca signalling in the apical dendrites, which, with calmodulin, upregulates specifically Nav1.6 channel-mediated persistent Na currents (I ) in the dendrites. This HFS-induced increase in dendritic I results in transient increases in the amplitude of excitatory postsynaptic potentials induced by both proximal SC and distal perforant path stimulation, leading to the enhanced probability of AP firing associated with decreased AP thresholds. Taken together, our study identifies dendritic I as a novel target for mediating activity-dependent modulation of dendritic integration and neuronal output.

Enhancement of dendritic persistent Na+ currents by mGluR5 leads to an advancement of spike timing with an increase in temporal precision

“…We recently reported that high-frequency stimulations (HFS; 100 Hz for 0.5 s) to Schaffer Collateral (SC) synapses trigger mGluR-dependent Ca 2+ release in apical dendrites of CA1-PN, which in turn induce calmodulin-dependent increase in persistent Na current (I Na,P ) that leads to E-S potentiation [ 32 ]. To investigate the effects of dendritic I Na,P increases on intrinsic excitability of CA1-PNs, we tested whether action potential (AP) firing in CA1-PNs evoked by depolarizing current injection is affected by HFS.…”

“…The activation of the group I mGluRs are coupled to G q protein-mediated Ca 2+ signaling pathways, which ultimately modulate various ion channels that shape the input-output relationship of neuronal network. We have recently demonstrate that high-frequency stimulation (HFS) of the Schaffer collateral pathway leads to the reliable activation of postsynaptic mGluR5 in CA1-PNs, producing the short-term potentiation of EPSP-to-spike (E-S) coupling [ 32 ]. We showed the involvement of persistent Na + currents (I Na,P ) in proximal apical dendrites in mGluR5-dependent E-S potentiation, but the role of dendritic I Na,P enhancement in intrinsic excitability and firing properties in CA1-PNs remains to be characterized.…”

Direction of TDCS current flow in human sensorimotor cortex influences behavioural learning

“…Instead, the increase in excitability could reflect activity-dependent changes in excitability that are not directly related to learning or retention processes. For example, repetitive activation of excitatory inputs to hippocampal pyramidal cells has been shown to increase persistent sodium currents in the post-synaptic dendrites [ 47 ]. The changes are caused by activation of metabotropic glutamate receptor-mediated calcium signalling and lead to enhanced dendritic excitability.…”

Reversible silencing of endogenous receptors in intact brain tissue using 2-photon pharmacology

“…Data are mean ± SEM; 2-way ANOVA, *P < 0.05, **P < 0.01; ns, not significant. The resolution for 2PE of alloswitch achieved under these experimental conditions was obtained by fitting to a Gaussian function (FWHM; 6.2 ± 2. onto the apical dendritic arbor, but not the somatic region, of CA1 neurons can induce persistent sodium conductance (43). However, further spatially resolved insight was not possible, because puffing of the agonist evokes an extended recruitment of receptors while it travels away from the ejection site.…”