The neural code between neocortical pyramidal neurons depends on neurotransmitter release probability

Abstract

Although signaling between neurons is central to the functioning of the brain, we still do not understand how the code used in signaling depends on the properties of synaptic transmission. Theoretical analysis combined with patch clamp recordings from pairs of neocortical pyramidal neurons revealed that the rate of synaptic depression, which depends on the probability of neurotransmitter release, dictates the extent to which firing rate and temporal coherence of action potentials within a presynaptic population are signaled to the postsynaptic neuron. The postsynaptic response primarily reflects rates of firing when depression is slow and temporal coherence when depression is fast. A wide range of rates of synaptic depression between different pairs of pyramidal neurons was found, suggesting that the relative contribution of rate and temporal signals varies along a continuum. We conclude that by setting the rate of synaptic depression, release probability is an important factor in determining the neural code.

Figure 1

Functional synaptic model. (A) Stimulation paradigm used to obtain the parameters for the model. (B) Postsynaptic potential generated by a regular spike train (Bottom), at a frequency of 23 Hz measured experimentally (Top; average more than 50 sweeps), and computed with the model (Middle). (C) Same as B for irregular spike train (different synaptic connection). Postsynaptic potential is computed using a passive membrane mechanism [τ_mem(dV/dt) = −V + R_inI_syn(t)] with an input resistance of 100MΩ. τ_rec is obtained by measuring the time of recovery for a synapse after stimulating it with high frequency burst (single exponential). Other parameters are determined by iteratively comparing model and experimental traces until the best match with the initial (R1), transition (R2 and others), and stationary responses is achieved. Parameters in B: τ_inact = 3 msec, τ_rec = 800 msec, U_SE = 0.67, A_SE = 250 pA, τ_mem = 50 msec. Parameters in C: τ_inact = 3 msec, τ_rec = 450 msec, U_SE = 0.55, A_SE = 530 pA, τ_mem = 30 msec.

Figure 2

Frequency-dependent synaptic depression. (A) Recorded EPSPs generated by presynaptic spike trains at various frequencies (same neuron, average of 20 sweeps). (B) Stationary EPSPs in 2 mM [Ca²⁺]_out (•) and 1.5 mM [Ca²⁺]_out (⧗), same synapse. The solid line shows the inverse relationship with frequency. This effect of lowering [Ca²⁺]_out on the limiting frequency was observed in all four synaptic connections tested. (C) Time-averaged membrane potential in postsynaptic neurons during the last four EPSPs, relative to resting potential as a function of presynaptic AP frequency (seven synapses; observed). (Bars = SD.)

Figure 3

Utilization of synaptic efficacy parameter determines signaling presynaptic firing rates. (A) The predicted spatially summated synaptic input from n = 500 presynaptic neurons firing Poisson trains as a function of their firing rates r. The corresponding analytical expression, derived from the model Eq. 1, reads I_post = A_SEn(rτ_inactU_SE/1 + rτ_rec U_SE). Represented are the lowest, highest, and mean values of U_SE, derived from 33 experimentally examined synaptic connections. (B) Predicted time-averaged membrane potential at different presynaptic spiking frequencies, computed from the model. Parameters: U_SE = 0.4, τ_rec = 700 msec, τ_inact = 3 msec, τ_mem = 25 msec. Superimposed are the experimental time-averaged membrane potentials from the neuron represented in C. (C) Experimentally recorded EPSPs generated by Poisson presynaptic spike trains at various frequencies. Single-sweep responses are represented. Arrows indicate the time window over which the time-averaged membrane potentials shown in B were determined. (Inset) The onset of the response to the 5-Hz Poisson spike train. Similar results were obtained from three synaptic connections.

Figure 4

Signaling of synchronized transitions in the activity of a population of presynaptic neurons. (A) Experimentally recorded EPSPs generated by a Poisson spike train undergoing transition (indicated by arrow) from 10 to 40 Hz. The average membrane potentials before and after the transition (indicated by dashed line) were equal to the third decimal point. (B1) Simulated postsynaptic current, generated by Poisson spike trains, of a population of 500 presynaptic neurons with synchronous transitions from 1 to 10 Hz and then to 40 Hz, together with the response of a pyramidal neuron when the simulated synaptic current was injected into the soma. A population signal emerged as the number of neurons in the presynaptic pool was increased. Parameters of the model are the same as in Fig. 3. (B2) The same as B1 but with lower value of U_SE and twice as large A_SE. (C) Average voltage response recorded from a postsynaptic neuron after stimulating the presynaptic neuron with the sequence of 200 different Poisson spike trains undergoing the same transitions as in B.

Figure 5

Changing the amount of synaptic utilization by APs. (A) Effect of pairing pre- and postsynaptic APs on the synaptic response to a 23-Hz train of presynaptic APs (experiment). The average response of 58 sweeps is shown before and 20 min after pairing. This effect is described in greater detail in (7). Pairing episodes were repeated 20 times every 30 sec. (B) Changing U_SE can mimic the effect of pairing. U_SE = 0.35 before pairing, U_SE = 0.67 after pairing. The rest of parameters are as in Fig. 1B. (C) Lowering extracellular calcium increases the rate of failures of the synaptic connection from 2.6 ± 2.17% (n = 19) to 21 ± 5.4% (n = 6) and slows the rate of synaptic depression. This effect has been recorded in 10 synaptic connections and is reversible (data not shown). Despite a marked decrease in the probability of release, the stationary EPSPs (last three EPSPs) are unaffected. Average responses (40 sweeps) to 30-Hz presynaptic APs are shown. (D) Two different synaptic connections selected to demonstrate that while the initial responses (low frequency) were markedly different, the stationary EPSPs (high frequency) were the same. The differences are due to different utilizations of efficacies (U_SE values) and not due to differences in absolute efficacies. Average responses (40 sweeps) to 23-Hz presynaptic APs are shown. (E) Redistribution of synaptic efficacy caused by acetylcholine (ACh). Bath application of 50 μM ACh reduced the initial (low frequency) responses (by 50–80%) and reduced the rate of depression for consecutive EPSPs, but had no effect on stationary EPSPs. This effect has been recorded in all 11 synaptic connections and reverses on washout of ACh (n = 9) or washing of a muscarinic receptor antagonist, atropine (n = 2). Average responses (30 sweeps) to 40-Hz presynaptic APs are shown. Concentrations as low as 10 μM were effective in reducing the low frequency EPSP by more than 10% (n = 3). Higher concentrations (above 200 μM) almost block transmission completely (n = 3). Maximum responses from A to E are normalized.