Calcium-permeable AMPA receptors mediate timing-dependent LTP elicited by low repeat coincident pre- and postsynaptic activity at Schaffer collateral-CA1 synapses

Abstract

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...

Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aβ Plaques

“…Interestingly, while also high repeat numbers of STDP stimulation (i.e., 100× 1:1 and 35× 1:4 protocols at 2 Hz) successfully induced t-LTP; these stronger protocols were neither more successful nor induced a higher magnitude of t-LTP (compare Figure 2 A and Figure 3 A). Since this mild physiologically relevant stimulation with 6× 1:1 or 6× 1:4 paradigms induced t-LTP in adult mice (this study), but are equally effective also in 1 month old juvenile mice [ 34 ], our results indicate that physiological maturation does not affect STDP in the hippocampus of normal control mice.…”

“…To explore STDP properties in adult AD model mice, we first had to establish STDP paradigms that successfully induce t-LTP in adult WT mice. To this aim we investigated in a first series of experiments a low repeat (6× at 0.5 Hz) STDP paradigm that we previously established in juvenile WT mice [ 34 ], to induce t-LTP in 6-month-old (adult) C57Bl6/J mice ( Figure 1 and Figure 2 A).…”