Fig. 7: Model showing the switch from t-LTD to t-LTP occurring with maturation at CA3–CA1 synapses of the hippocampus.

a At P13–21, a known presynaptic form of t-LTD is induced by a post-pre single-spike pairing protocol. In this presynaptically expressed form of t-LTD, postsynaptic action potentials activate voltage-dependent Ca²⁺ channels (VDCCs) and the presynaptically released glutamate activates postsynaptic mGluR, activating PLC and provoking Ca²⁺ release from internal stores and DAG production, which serves a precursor for endocannabinoids (eCBs) synthesis. For t-LTD, eCB signal is necessary to activate CB₁ receptors to facilitate d-serine release from astrocytes. Together with the glutamate released from presynaptic neurons, this d-serine is known to activate preNMDAR on Schaffer collateral boutons, leading to an increase in presynaptic Ca²⁺, calcineurin activation and synaptic depression. Modified from ref. ^12,13. b In the present study, it has been found that at P35-32, t-LTD is not observed and instead the same protocol (a post-pre protocol) induces presynaptic t-LTP. At this developmental stage, the probability of release has considerably decreased owing to an increase in adenosine release from astrocytes compared with P13–21. Also different to t-LTD induced by the same protocol at P13–21, eCB signaling and NMDAR are not required for presynaptic t-LTP. For the induction of t-LTP, postsynaptic action potentials activates voltage-dependent Ca²⁺ channels (VDCCs) causing calcium release from internal stores, inducing NO synthesis. The NO signal leads to the activation of astrocytes to release glutamate and/or adenosine to activate presynaptic mGluR5 and A₁R respectively on Schaffer collateral boutons. A₁R activation considerably reduces neurotransmitter probability release whereas mGluR5 activation leads to a long-lasting increase in glutamate release and synaptic potentiation.