Slow AMPA receptors in hippocampal principal cells

Abstract

SummaryGlutamate receptor ion channels such as the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor mediate the majority of fast excitatory neurotransmission in the vertebrate CNS. AMPA receptors canonically provide the fast, millisecond component of the synaptic current. However, we found that about two-thirds of principal cells in the mouse hippocampus express AMPA receptors that do not desensitize and stay active for up to half a second. These receptors are expressed at synapses with a sparse but flat spatial distribution. The resulting increase in charge transfer allows single connections to reliably trigger action potentials. Biophysical and pharmacological observations imply that slow AMPA receptors incorporate γ-8 and other auxiliary proteins, and their activation lengthens individual miniature synaptic currents. Synaptic connections harboring slow AMPARs should have unique roles in hippocampal function.

Slow excitatory synaptic currents generated by AMPA receptors

“…Non-desensitizing AMPA responses accumulate with repetitive stimulation in CA1 pyramidal cells, and to a lesser extent in CA3. Repetitive stimulation at as low as 5 Hz can generate long-lived depolarization, and the magnitude of the slow current is frequency-dependent (Pampaloni et al 2021) as observed in other cases (Wu et al 2004;Combe et al 2018).…”

“…To complicate the picture, a variety of transporters with different glutamate affinities are present (Tzingounis & Wadiche, 2007), in glial cells (Rose et al 2017) as well in extrasynaptic (Scimemi et al 2009) and synaptic (Tong & Jahr, 1994) regions. In general, slow AMPA currents are more prominent in younger animals (Taschenberger et al 2002;Renden et al 2005;Stincic & Frerking, 2015;Pampaloni et al 2021). A result that could unify this point was found in the rat calyx of Held synapse in which TBOA had an effect on postnatal day (P)8-P10 synapses but not on P16 synapses, indicating a strong developmental regulation of EAATs (Renden et al 2005).…”

“…Early work using fast agonist perfusion on AMPA receptors presented a coherent picture of fast activation. Whether the preparation was recombinant receptors, those in primary hippocampal cultures or those extracted from the dendrites of principal cells in acute brain Properties of slow AMPA receptors denoted with an asterisk are from Pampaloni et al (2021). A high affinity for glutamate is inferred from the slow decay.…”

“…Slow AMPA receptors, with kinetics >100 ms, defined by GYKI 52466 inhibition (Table 1) and sensitivity to auxiliary subunit perturbation (Fig. 2), are widespread in principal cells, with a mosaic distribution (Pampaloni et al 2021). Non-desensitizing AMPA responses accumulate with repetitive stimulation in CA1 pyramidal cells, and to a lesser extent in CA3.…”

“…The kainate receptor current at the mossy fibre synapse (Castillo et al 1997;Vignes & Collingridge, 1997) contributes to the detonator property of this input to dominate the firing of CA3 pyramidal cells (Henze et al 2002;Sachidhanandam et al 2009). It appears that the slow AMPA current can play a similar role in CA1 (Pampaloni et al 2021). Intriguingly, block of the slow accumulating current by the kainate receptor-specific competitive antagonist UBP 310 is incomplete (Pinheiro et al 2013), reflecting either the inconsistency of the blocker across different kainate receptor subtypes, but also perhaps reflecting a contribution of slow AMPA receptors in CA3 pyramidal cells (Pampaloni et al 2021).…”