Sustained postsynaptic kainate receptor activation downregulates AMPA receptor surface expression and induces hippocampal LTD

Abstract

Summary It is well established that long-term depression (LTD) can be initiated by either NMDA or mGluR activation. Here we report that sustained activation of GluK2 subunit-containing kainate receptors (KARs) leads to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis and induces LTD of AMPARs (KAR-LTD AMPAR ) in hippocampal neurons. The KAR-evoked loss of surface AMPARs is blocked by the ionotropic KAR inhibitor UBP 310 indicating that KAR-LTD AMPAR requires KAR channel activity. Interestingly, however, blockade of PKC or PKA also reduces GluA2 surface expression and occludes the effect of KAR activation. In acute hippocampal slices, kainate application caused a significant loss of GluA2-containing AMPARs from synapses and long-lasting depression of AMPAR excitatory postsynaptic currents in CA1. These data, together with our previously reported KAR-LTP AMPAR , demonstrate that KARs can bidirectionally regulate synaptic AMPARs and synaptic plasticity via different signaling pathways.

Kainate and AMPA receptors in epilepsy: Cell biology, signalling pathways and possible crosstalk

“…Conversely, we have recently reported that sustained KAR stimulation can induce a downregulation of surface expressed AMPARs, as it does for KARs, in both cultured hippocampal neurons and in acute slices (KAR-LTD AMPAR ) (Nair et al, 2020) (Figure 5).…”

“…As for KAR-LTP AMPAR , KAR-LTD AMPAR requires GluK2 subunit-containing KARs. Moreover, the KAR-evoked loss of surface AMPARs is prevented by the antagonist UBP310, which blocks KAR channel activity (Dolman et al, 2005;Grosenbaugh et al, 2018;Petrovic et al, J o u r n a l P r e -p r o o f 2017; Pinheiro et al, 2013), but is not blocked by the G-protein inhibitor pertussis toxin (Nair et al, 2020). Thus, as postulated for the bidirectional autoregulation of KARs, the cell biological mechanisms underlying KAR-LTP AMPAR and KAR-LTD AMPAR differ insofar as KAR-LTP AMPAR is mediated via the metabotropic signalling pathway whereas KAR-LTD AMPAR is mediated by ionotropic KAR signalling.…”

GluK2 Q/R editing regulates kainate receptor signalling to modulate AMPA receptor synaptic expression and plasticity

“…A critical role for metabotropic KAR signaling is regulation of both KAR and AMPAR surface expression. For example, depending on the extent of activation, KARs can enhance or reduce AMPAR surface expression to evoke LTP or LTD via metabotropic signalling (23, 34). Our data also show that GluK2 editing impacts on NMDAR-induced LTP at Schaffer collateral synapses in CA1 with GluK2(Q) mice exhibiting reduced LTP.…”

“…KAR surface expression is activity-dependent and bidirectionally regulated (23, 29-33). Furthermore, activation of KARs can also up- or down regulate AMPAR surface expression and plasticity (23, 34). For example, in cultured hippocampal neurons transient, selective activation of GluK2-containing KARs increases AMPAR surface expression and at Schaffer collateral-CA1 synapses in hippocampal slices GluK2-containing KARs can induce AMPAR long-term potentiation (KAR-LTP AMPAR ) via a pertussis toxin-sensitive metabotropic signalling pathway (23).…”

“…For example, in cultured hippocampal neurons transient, selective activation of GluK2-containing KARs increases AMPAR surface expression and at Schaffer collateral-CA1 synapses in hippocampal slices GluK2-containing KARs can induce AMPAR long-term potentiation (KAR-LTP AMPAR ) via a pertussis toxin-sensitive metabotropic signalling pathway (23). In contrast, sustained activation of KARs in cultured hippocampal neurons reduces surface expression of AMPARs and induces AMPAR long-term depression (KAR-LTD AMPAR ) in CA1 neurons in hippocampal slices, an effect that is lost in the absence of GluK2 (34). These results highlight the importance of GluK2-containing KARs as modulators of AMPAR-mediated synaptic transmission.…”