In the neocortex, each neuron receives thousands of synaptic inputs distributed across an extensive dendritic tree. Although postsynaptic processing of each input is known to depend on its dendritic location1,2,3,4,5,6,7,8, it is unclear whether activity-dependent synaptic modification is also location-dependent. Here we report that both the magnitude and the temporal specificity of spike-timing-dependent synaptic modification9,10,11,12,13,14,15,16,17 vary along the apical dendrite of rat cortical layer 2/3 pyramidal neurons. At the distal dendrite, the magnitude of long-term potentiation is smaller, and the window of pre-/postsynaptic spike interval for long-term depression (LTD) is broader. The spike-timing window for LTD correlates with the window of action potential-induced suppression of NMDA (N-methyl-d-aspartate) receptors; this correlation applies to both their dendritic location-dependence and pharmacological properties. Presynaptic stimulation with partial blockade of NMDA receptors induced LTD and occluded further induction of spike-timing-dependent LTD, suggesting that NMDA receptor suppression underlies LTD induction. Computer simulation studies showed that the dendritic inhomogeneity of spike-timing-dependent synaptic modification leads to differential input selection at distal and proximal dendrites according to the temporal characteristics of presynaptic spike trains. Such location-dependent tuning of inputs, together with the dendritic heterogeneity of postsynaptic processing, could enhance the computational capacity of cortical pyramidal neurons.
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We thank P. Ascher, G. Bi, L. Chen, M. Frerking, E. Isacoff, R. Kramer and R. Zucker for helpful discussions, and K. Arendt, K. Borges, N. Caporale and C. Nam for technical assistance. This work was supported by grants from the National Eye Institute and the Grass Foundation. R.C.F. is a recipient of the Howard Hughes Predoctoral Fellowship.
The authors declare that they have no competing financial interests.
This file contains Supplementary Figures 1 to 6 and Legends. Supplementary Figure 1: This figure demonstrates that spike-timing-dependent LTD is independent of GABAA receptor-mediated inhibition both at proximal and distal dendritic locations. Supplementary Figure 2: This figure summarizes whole-cell recordings from apical dendrites of layer 2/3 pyramidal neurons. Spike amplitude and half-width are compared to the size and extent of the AP-EPSP suppression time window measured at different dendritic locations. Supplementary Figure 3: This figure shows the time windows for AP-induced suppression of AMPAR-EPSPs and NMDAR-EPSPs recorded at proximal and distal dendrites. The time course of suppression under both conditions is similar between dendritic and somatic recordings (see Figure 2). Supplementary Figure 4: This figure shows the effects on NMDAR-EPSP suppression and LTD of viral expression of a peptide corresponding to a region of the NR2A subunit critical for calcineurin-dependent NMDAR desensitization. Supplementary Figure 5: This figure shows Ca2+ imaging of apical dendrites from layer 2/3 pyramidal neurons. Distal regions of the dendrite exhibit higher amplitudes of AP-triggered Ca2+ increase than proximal regions. Enhancing the width of the back-propagating action potential with the transient K+ channel blocker 4-AP leads to larger Ca2+ influx at proximal dendrites. Supplementary Figure 6: This figure presents further analyses of the model shown in Figure 5. Example spike trains are shown, along with the cross-correlation of pre- and postsynaptic spike trains, and a four-compartment version of the model in Figure 5. (DOC 622 kb)
This file describes the model of dendritic inhomogeneity of STDP used for the simulations in Figure 5 and Supplementary Figure 6. (DOC 64 kb)
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Frontiers in Neuroscience (2019)
PLOS Computational Biology (2019)
Cerebral Cortex (2019)