(A) Diagram, NEURON model of a reconstructed CA1 pyramidal cell (Migliore et al., 1999) (ModelDB 2796; variable time step dt, t = 34°C). 50 excitatory inputs (blue dots) generate bi-exponential conductance change (rise and decay time, 1 ms and 20 ms, respectively) stochastically, in accord with Pr. Traces, simulated somatic response to paired-pulse stimuli (50 ms apart), with Pr distributed either uniformly randomly (black), or in accord with the distance-dependent trend (as in Figure 1C; red), and both Pr and synaptic density trends (as in Figure 2E, blue; same average Pr = 0.36 ). (B) Summary of simulation tests in (A); dots, individual runs (n = 100); bars, mean EPSP amplitude (left, mean ± SEM: 2.90 ± 0.060, 3.27 ± 0.061, 3.20 ± 0.068, for the three conditions, respectively, as indicated) and paired-pulse ratios (right, mean ± SEM: 1.96 ± 0.047, 1.57 ± 0.036, 1.52 ± 0.0437, notation as above) are shown; ***p<0.005. (C) Input-output spiking rate relationship over the physiological range of input firing frequencies (per axon, bottom axis; total, top axis); hollow circles, uniform distribution of Pr; solid symbols, Pr follows the distance-dependent trend (as in Figure 1C); mean ± SEM are shown (n = 100 simulation runs). (D) Trace: A characteristic cell spiking burst (model as in A) in response to a Poisson-process afferent spiking input (~50 Hz per synapse) incorporating the experimental kinetics of short-term plasticity (STP) at CA3-CA1 synapses (Mukunda and Narayanan, 2017) (see Figure 4—figure supplement 1C–F for detail). Graph: Input-output spiking rate relationship across the physiological range of average input firing frequencies, with experimental STP incorporated; other notations as in (C); the top abscissa scale is nonlinear because STP affects average Pr in a biphasic, non-monotonous manner (see Figure 4—figure supplement 1C).