Postsynaptic, not presynaptic NMDA receptors are required for spike-timing-dependent LTD induction

Long-term depression at synapses between L4 and L2/3 neurons in somatosensory cortex is thought to require presynaptic NMDARs. In contrast, the present work finds that genetic deletion of postsynaptic but not presynaptic NMDARs blocks LTD and that the action of postsynaptic NMDARs appears to be metabotropic rather than ionotropic. Long-term depression (LTD) between cortical layer 4 spiny stellate cells and layer 2/3 pyramidal cells requires the activation of NMDA receptors (NMDARs). In young rodents, this form of LTD has been repeatedly reported to require presynaptic NMDARs for its induction. Here we show that at this synapse in the somatosensory cortex of 2- to 3-week-old rats and mice, postsynaptic, not presynaptic NMDARs are required for LTD induction. First, we find no evidence for functional NMDARs in L4 neuron axons using two-photon laser scanning microscopy and two-photon glutamate uncaging. Second, we find that genetic deletion of postsynaptic, but not presynaptic NMDARs prevents LTD induction. Finally, the pharmacology of the NMDAR requirement is consistent with a nonionic signaling mechanism.