Developmental Spike Timing-Dependent Long-Term Depression Requires Astrocyte d-Serine at L2/3-L2/3 Synapses of the...

Spike timing-dependent plasticity (STDP) is a learning rule important for synaptic refinement and for learning and memory during development. While different forms of presynaptic t-LTD have been deeply investigated, little is known about the mechanisms of somatosensory cortex postsynaptic t-LTD. In the present work, we investigated the requirements and mechanisms for induction of developmental spike timing-dependent long-term depression (t-LTD) at L2/3-L2/3 synapses in the juvenile mouse somatosensory cortex. We found that postnatal day (P) 13-21 mice of either sex show t-LTD at L2/3-L2/3 synapses induced by pairing single presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz) that is expressed postsynaptically and requires the activation of ionotropic postsynaptic NMDA-type glutamate receptors containing GluN2B subunits. In addition, it requires postsynaptic Ca²⁺, Ca²⁺ release from internal stores, calcineurin, postsynaptic endocannabinoid synthesis, activation of CB₁ receptors, and astrocytic signaling to release the gliotransmitter d-serine to activate postsynaptic NMDARs to induce t-LTD. These results show direct evidence of the mechanism involved in developmental postsynaptic t-LTD at L2/3-L2/3 synapses, revealing a central role of astrocytes and their release of d-serine in its induction.