Cooperative coincidence detectors control mixed pre-and postsynaptic expression of spike-timing dependent plasticity at the cerebellar input stage

Excitatory central synapses show a special form of persistent change, spike-timing dependent plasticity (STDP), in which long-term potentiation and depression (LTP and LTD) are related to the relative phase of occurrence of EPSPs and action potentials. At the cerebellar mossy fiber - granule cell synapse, LTP and LTD have been previously related to the duration and frequency of input busts but their EPSP-spike phase sensitivity was unknown. Here we show that EPSP-spike pairing on the 6 Hz band can reliably induce STDP in this synapse. LTP was confined to the +5/+20 ms time-window, while LTD occurred at longer positive phases and at negative phases revealing a high temporal precision for LTP induction. STDP as a whole required NMDA receptor activation and calcium release from intracellular stores, but LTP also required mGluR activation and higher calcium levels. Importantly, STDP was 2–3 times larger than any forms of long-term synaptic plasticity previously reported at this same synapse (LTP:+61.4 % ± 20.2 %, n = 5, t < 0.05; LTD:-50.6 % ± 12.6 %, n = 5, t < 0.05). While LTP and LTD induced by modulated burst duration and frequency were uniquely expressed by a release probability change, STDP showed a mixed pre- and postsynaptic expression attested by consistent changes in EPSC amplitude and coefficient of variation, EPSC paired-pulse ratio (PPR; LTP:-32.3 % ± 4.9 %, n = 5, t < 0.001; LTD:+21.0 % ± 14.9 %, n = 5, t < 0.05) and minis amplitude (LTP:+23.4 % ± 9.9 %, n = 5, t < 0.05; LTD:-16.1 % ± 5.2 %, n = 5, t < 0.05) and frequency (LTP:+18.1 % ± 8.7 %, n = 5, t < 0.05; LTD:-30.7 % ± 8.6 %, n = 5, t < 0.05). Therefore STDP appears a powerful form of plasticity that binds LTP to the mossy fiber burst phase on the millisecond time-scale and could control granular layer functions binding it tightly to ongoing brain temporal dynamics.