18The structural organization of excitatory inputs that supports spike-timing-dependent plasticity 19 (STDP) remains unknown. Here we performed a spine STDP protocol using two-photon 20 glutamate uncaging (pre) paired with postsynaptic spikes (post). We found that pre-post pairings 21 that trigger LTP (t-LTP) produce shrinkage of the activated spine neck and increase in synaptic 22 32 Dendritic spines, the main recipient of excitatory information in the brain 1 , are tiny protrusions 33 with a small head (~1 µm in diameter and <1 fL volume) separated from the dendrite by a 34 slender neck. Spines can undergo structural remodeling that is tightly coupled with synaptic 35 function 1, 2, 3, 4 , and are the preferential site for the induction of long-term potentiation (LTP) 4, 5, 36 6, 7 and long-term depression (LTD) 8 , thought to be the underlying mechanisms for learning and 37 memory in the brain 9 . A variation of LTP and LTD has been described in pyramidal neurons 38 that involves the pairing of pre-and postsynaptic action potentials, known as spike-timing 39 dependent plasticity (STDP) 10, 11 . In this process, the timing between pre-and postsynaptic 40 action potentials modulates synaptic strength, triggering LTP or LTD 11 . The sign and magnitude 41 of the change in synaptic strength depends on the relative timing between spikes of two 42 connected neurons (the pre-and postsynaptic neuron 12 ). The STDP learning rules and their 43 dependency on postsynaptic dendritic depolarization 13, 14 , firing rate 13 , and somatic distance of 44 excitatory inputs 14, 15, 16 have been extracted from studies using connected neuronal pairs or by 45 using extracellular stimulating electrodes, but the precise location and structural organization of 46 excitatory inputs capable of supporting STDP at its minimal functional unit -the dendritic spine 47 -are unknown. 48 Activity-dependent spine morphological changes (spine head 4 , neck 2 , or both 17 ) have been 49 correlated with changes in synaptic strength in cortical pyramidal neurons by mechanisms 50 involving biochemical and electrical spine changes 1, 6 . Thus, here we asked what patterns of 51 activity and structural organization of excitatory synaptic inputs support the generation of t-LTP 52 and t-LTD, and which morphological, biophysical and molecular changes observed in dendritic 53 spines can account for the induction of t-LTP and t-LTD? 54 4To induce synapse-specific STDP we performed a protocol whereby two-photon (2P) uncaging 55 of a caged glutamate (MNI-glutamate 3 ) at a single spine -to mimic synaptic release -is 56 preceded or followed in time (STDP timing window 11 ) by a backpropagating action potential 57 (bAP) to trigger t-LTP or t-LTD, respectively. Two-photon uncaging of a caged glutamate at a 58 single spine triggered excitatory postsynaptic potentials (uncaging(u)EPSP) that were recorded in 59 the soma of layer 5 (L5) pyramidal neurons before and after the induction of STDP, while the 60 morphology of the activat...
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