Abstract
The efficacy of neocortical synapses to transmit during bursts of action potentials (APs) increases during development but the underlying mechanisms are largely unclear. We investigated synaptic efficacy at synapses between layer 5 pyramidal neurons (L5PNs) during development, using paired recordings, presynaptic two-photon Ca2+ imaging, and numerical simulations. Our data confirm a developmental increase in paired-pulse ratios (PPRs). Independent of age, Ca2+ imaging revealed no AP invasion failures and linear summation of presynaptic Ca2+ transients, making differences in Ca2+ signaling an unlikely reason for developmental changes in PPR. Cumulative excitatory postsynaptic current (EPSC) amplitudes indicate that neither the size of the readily-releasable pool (RRP) nor replenishment rates were different between age groups, while the time-courses of depression differed significantly. At young synapses, EPSCs depressed rapidly to near steady-state during the first four APs, and synaptic failures (Fsyn) increased from 0 to 30%. At mature synapses this drop was significantly slower and strongly biphasic, such that near steady-state depression was reached not before 18 APs with Fsyn remaining between 0 and 5%. While young synapses reliably transmitted during pairs of APs, albeit with strong depression, mature synapses maintained near 100% transfer efficacy with significantly less depression during high-frequency bursts of APs. Our analysis indicates that at mature synapses a replenishment pool (RepP) is responsible for their high efficacy during bursting activity, while this RepP is functionally immature at young synapses. Hence, our data provide evidence that the functional maturation of a RepP underlies increasing synaptic efficacy during the development of an excitatory cortical synapse.
Highlights
Synaptic efficacy is the capacity of a presynaptic input to influence the postsynaptic neuron (López, 2002)
We found paired-pulse depression in both age windows, albeit with significantly less depression at mature than at young synapses (PPR = 0.54, 0.45–0.70, P < 0.001, Mann–Whitney-U rank sum test (MWU) test; Figures 1B,C), which is consistent with a previous observation at these synapses (Frick et al, 2007)
We found that application of γDGG (1–2 mM) clearly reduced excitatory postsynaptic current (EPSC) amplitudes (A1 reduced to 36%, 17–39%, n = 5), while paired-pulse ratios (PPRs) remained unaffected (0.81, 0.61–0.86, n = 5, P = 0.822; Figure 1C) in comparison to control
Summary
Synaptic efficacy is the capacity of a presynaptic input to influence the postsynaptic neuron (López, 2002). A synapse can be considered as a device that receives trains of presynaptic action potentials (APs) and affects the postsynaptic output through graded analog responses (London et al, 2002). In this process, synapses do not transmit each AP identically but do so in a manner that is dependent on the history of activity of the synapse. During trains of APs, synaptic transmission may either show short term depression (STD) or short term facilitation (STF), sometimes referred to as Maturation of Vesicle Replenishment ‘‘phasic’’ or ‘‘tonic’’ synapses, respectively (Pan and Zucker, 2009; Neher and Brose, 2018). Either synaptic depression or synaptic facilitation result (Quastel, 1997; Neher and Brose, 2018; Schmidt, 2019)
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