High-frequency stimulation induced long-term potentiation (LTP) and low-frequency stimulation induced LTD are considered as cellular models of memory formation. Interestingly, spike timing-dependent plasticity (STDP) can induce equally robust timing-dependent LTP (t-LTP) and t-LTD in response to low frequency repeats of coincident action potential (AP) firing in presynaptic and postsynaptic cells. Commonly, STDP paradigms relying on 25–100 repeats of coincident AP firing are used to elicit t-LTP or t-LTD, but the minimum number of repeats required for successful STDP is barely explored. However, systematic investigation of physiologically relevant low repeat STDP paradigms is of utmost importance to explain learning mechanisms in vivo. Here, we examined low repeat STDP at Schaffer collateral-CA1 synapses by pairing one presynaptic AP with either one postsynaptic AP (1:1 t-LTP), or a burst of 4 APs (1:4 t-LTP) and found 3–6 repeats to be sufficient to elicit t-LTP. 6× 1:1 t-LTP required postsynaptic Ca2+ influx via NMDARs and L-type VGCCs and was mediated by increased presynaptic glutamate release. In contrast, 1:4 t-LTP depended on postsynaptic metabotropic GluRs and ryanodine receptor signaling and was mediated by postsynaptic insertion of AMPA receptors. Unexpectedly, both 6× t-LTP variants were strictly dependent on activation of postsynaptic Ca2+-permeable AMPARs but were differentially regulated by dopamine receptor signaling. Our data show that synaptic changes induced by only 3–6 repeats of mild STDP stimulation occurring in ≤10 s can take place on time scales observed also during single trial learning.

19 20 21 22 23 24 25 26 2 27 Abstract 2829 Activity-dependent changes of synaptic transmission in neuronal circuits are thought to represent the 30 cellular mechanism of memory formation in the brain. Experimentally, such changes can be elicited by 31 repeated high-frequency synaptic stimulation inducing long-term potentiation (LTP), or by long-lasting 32 low frequency stimulation, that induces long-term depression (LTD). In contrast, spike timing-33 dependent plasticity (STDP) can induce equally robust and long-lasting timing-dependent LTP (t-LTP) in 34 response to low frequency repeats of coincident individual action potentials first in the presynaptic and 35 then in the postsynaptic neuron. Conversely, this stimulation leads to t-LTD if the postsynaptic precedes 36 the presynaptic action potential. Importantly, STDP is best suited to investigate synaptic plasticity 37 mechanisms at the single cell level. Commonly, STDP paradigms relying on 25-100 repeats (comprising 38 several minutes of synaptic stimulation) of coincident pre-and postsynaptic spike firing are used to elicit 39 robust t-LTP or t-LTD. However, the minimum number of repeats required for successful STDP induction, 40 which could account for single trial learning in vivo (comprising only a few seconds), is barely explored.41 Here, we examined low repeat STDP at Schaffer collateral-CA1 synapses by pairing one presynaptic 42 action potential with either one postsynaptic action potential (1:1 t-LTP), or with a burst of 4 43 postsynaptic action potentials (1:4 t-LTP). Six repeats were sufficient to elicit 1:1 t-LTP while only three 44 repeats were required for 1:4 t-LTP. Postsynaptic Ca 2+ elevation for 1:1 t-LTP required Ca 2+ influx via 45 NMDARs and voltage gated calcium channels (VGCCs), but depended in case of 1:4 t-LTP on activation 46 of metabotropic GluR and ryanodine receptor mediated Ca 2+ release from internal stores. Surprisingly, 47 both t-LTP variants were strictly dependent on a transient activation of postsynaptic Ca 2+ -permeable 48 AMPARs, although the locus of t-LTP expression was presynaptic for low repeat 1:1 t-LTP but depended 49 on postsynaptic insertion of new GluA1 containing-AMPARs in case of low repeat 1:4 t-LTP. Both t-LTP 50 forms were regulated differentially by dopamine receptor subtype 1 (D1R) and D2R activation, but 51 occurred independent from BDNF/TrkB signaling. Our data suggest, that learning relevant long-lasting 52 synaptic changes can be induced by only 3-6 repeats of mild STDP stimulation that can occur in < 10 s 53 and could therefore underlie single trial learning in vivo.3 54 55 Introduction 56 57 Long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission can be observed 58 in response to repetitive activation of synapses and are believed to represent cellular models of learning 59 and memory processes in the brain (see e.g., 1, 2, 3). While LTP leads to a stable enhancement of 60 synaptic transmission between connected neurons, LTD yields a long-lasting decrease in synaptic 61 resp...