NATURE NEUROSCIENCE VOLUME 12 | NUMBER 10 | OCTOBER 2009 1219 BRIEF COMMUNICATIONS Spike timing–dependent plasticity (STDP) is a ubiquitous Hebbian learning rule 1 in which synaptic modification depends on the order of pre- and postsynaptic spiking in time windows of a few tens of milliseconds. If the presynaptic input is active before the postsynaptic spike, then potentiation occurs, as was originally predicted by Hebb 2 , whereas synaptic depression is induced if this order is reversed 3–5 . The computational consequences of this local learning rule depends on the architecture and circuit dynamics of the network in which the synapses are embedded. The hippocampus, which has an estab- lished role in memory, is an attractive experimental system in which to study such interactions, as both the network architecture and circuit dynamics are well characterized 6,7 . CA1 pyramidal neurons receive local input via the Schaffer collaterals from CA3 and external input from the entorhinal cortex via perforant path fibers (the ‘direct’ tem- pero-ammonic pathway) 8 . During spatial learning, the hippocampal network engages in rhythmic theta activity, during which hippo- campal principal neurons receive rhythmic perisomatic inhibition at 4–6 Hz 9 . To mimic this network state, we subjected individual CA1 pyrami- dal neurons to a rhythmic inhibitory conductance using dynamic clamp while depolarizing the cell to fire a single action potential at the peak of each theta cycle (Fig. 1a,b; see Supplementary Methods). To test how the external tempero-ammonic input controls spike tim- ing in CA1 pyramidal cells during theta oscillations, we stimulated the tempero-ammonic input at different theta phases and recorded the effects on postsynaptic spike timing. We found that, depend- ing on the timing of the tempero-ammonic input, the spike times The timing of external input controls the sign of plasticity at local synapses Jeehyun Kwag & Ole Paulsen The method by which local networks in the brain store information from extrinsic afferent inputs is not well understood. We found that the timing of afferent input can bidirectionally control the sign of spike timing–dependent plasticity at local synapses in rat hippocampus. This mechanism provides a means by which temporal information in external input can be encoded in the local matrix of synaptic weights. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. Correspondence should be addressed to O.P. (ole.paulsen@dpag.ox.ac.uk). Received 25 May; accepted 22 July; published online 6 September 2009; doi:10.1038/nn.2388 4 nS 20 mV –100 0 –200 Time (ms) 200 ms 4 nS 20 mV –40 –20 0 20 40 Advancement/delay (ms) Advancement/delay (ms) –200 –150 –100 –50 0 Time of EPSP (ms) a b c d TA stim Rec –30 –20 –10 0 30 20 10 0 Figure 1 Tempero-ammonic input controls postsynaptic spike timing of CA1 pyramidal neurons during theta oscillation. ( a) Experimental set-up. A CA1 neuron with a recording electrode at the soma (Rec) and an extracellular electrode stimulating tempero-ammonic input (TA stim) is shown. ( b) Example voltage traces during theta oscillation produced by conductance clamp (black trace, minimum inhibitory conductance upwards). Without synaptic perturbation, neuron spiked near the peak of oscillation (gray, dashed line). Tempero-ammonic input stimulation on the ascending phase of oscillation (light gray bar) advanced postsynaptic spikes (light gray trace). Tempero-ammonic input stimulation on the descending phase of oscillation (black bar) delayed postsynaptic spikes (black trace). (c) Superimposed voltage traces of postsynaptic spikes (light gray to black bars, time of postsynaptic spike) with tempero-ammonic input stimulation at different times during theta oscillation (black to light gray bars). Note the reversal and time compression of output relative to input (gray scale). (d) Plot of spike time advancement and delay as a function of time of tempero-ammonic stimulation for the cell shown in b and c. Data are mean ± s.d. of ten postsynaptic spike times for each tempero-ammonic stimulation time. Inset, maximum spike time delay (black bar) and advancement (light gray bar) induced by tempero-ammonic stimulation (n = 7). EPSP, excitatory postsynaptic potential. © 2009 Nature America, Inc. All rights reserved.