Abstract
Spike-timing-dependent long-term depression (t-LTD) of glutamatergic layer (L)4-L2/3 synapses in developing neocortex requires activation of astrocytes by endocannabinoids (eCBs), which release glutamate onto presynaptic NMDA receptors (preNMDARs). The exact function of preNMDARs in this context is still elusive and strongly debated. To elucidate their function, we show that bath application of the eCB 2-arachidonylglycerol (2-AG) induces a preNMDAR-dependent form of chemically induced LTD (eCB-LTD) in L2/3 pyramidal neurons in the juvenile somatosensory cortex of rats. Presynaptic Ca2+ imaging from L4 spiny stellate axons revealed that action potential (AP) evoked Ca2+ transients show a preNMDAR-dependent broadening during eCB-LTD induction. However, blockade of voltage-dependent Ca2+ channels (VDCCs) did not uncover direct preNMDAR-mediated Ca2+ transients in the axon. This suggests that astrocyte-mediated glutamate release onto preNMDARs does not result in a direct Ca2+ influx, but that it instead leads to an indirect interaction with presynaptic VDCCs, boosting axonal Ca2+ influx. These results reveal one of the main remaining missing pieces in the signaling cascade of t-LTD at developing cortical synapses.
Highlights
Presynaptic NMDA receptors have important functions in synaptic transmission, information processing, and long-term plasticity in several regions of the brain [1–3]
Blockade of voltage-dependent Ca2+ channels (VDCCs) did not uncover direct preNMDAR-mediated Ca2+ transients in the axon. This suggests that astrocyte-mediated glutamate release onto preNMDARs does not result in a direct Ca2+ influx, but that it instead leads to an indirect interaction with presynaptic VDCCs, boosting axonal Ca2+ influx
We suggested that timing-dependent long-term depression (t-LTD) in the developing rat barrel cortex requires eCB-dependent activation of astrocytes, which results in the release of glutamate onto preNMDARs [8, 9]
Summary
Presynaptic NMDA receptors (preNMDARs) have important functions in synaptic transmission, information processing, and long-term plasticity in several regions of the brain [1–3]. PreNMDARs are thought to be required for the induction of spike-timing-dependent LTD (t-LTD) at developing neocortical synapses [4–7]. We suggested that t-LTD in the developing rat barrel cortex requires eCB-dependent activation of astrocytes, which results in the release of glutamate onto preNMDARs [8, 9]. We showed that astrocyte activity alone is not sufficient for the induction of LTD. Simultaneous presynaptic APs concomitant with astrocyte activation are required [8]. This suggests that axonal APs interact with preNMDARs in a yet unknown way leading to the induction of t-LTD
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