Predictable Fluctuations in Excitatory Synaptic Strength Due to Natural Variation in Presynaptic Firing Rate.

Many controlled studies have demonstrated how postsynaptic responses to presynaptic spikes are not constant but depend on short-term synaptic plasticity (STP) and the detailed timing of presynaptic spikes. However, the effects of short-term plasticity (depression and facilitation) are not limited to short, subsecond timescales. The effects of STP appear on long timescales as changes in presynaptic firing rates lead to changes in steady-state synaptic transmission. Here, we examine the relationship between natural variations in the presynaptic firing rates and spike transmission Using large-scale spike recordings in awake male and female mice from the Allen Institute Neuropixels dataset, we first detect putative excitatory synaptic connections based on cross-correlations between the spike trains of millions of pairs of neurons. For the subset of pairs where a transient, excitatory effect was detected, we use a model-based approach to track fluctuations in synaptic efficacy and find that efficacy varies substantially on slow (∼1 min) timescales over the course of these recordings. For many connections, the efficacy fluctuations are correlated with fluctuations in the presynaptic firing rate. To understand the potential mechanisms underlying this relationship, we then model the detailed probability of postsynaptic spiking on a millisecond timescale, including both slow changes in postsynaptic excitability and monosynaptic inputs with short-term plasticity. The detailed model reproduces the slow efficacy fluctuations observed with many putative excitatory connections, suggesting that these fluctuations can be both directly predicted based on the time-varying presynaptic firing rate and, at least partly, explained by the cumulative effects of STP. The firing rates of individual neurons naturally vary because of stimuli, movement, and brain state. Models of synaptic transmission predict that these variations in firing rates should be accompanied by slow fluctuations in synaptic strength because of short-term depression and facilitation. Here, we characterize the magnitude and predictability of fluctuations in synaptic strength using large-scale spike recordings. For putative excitatory connections from a wide range of brain areas, we find that typical synaptic efficacy varies as much as ∼70%, and in many cases the fluctuations are well described by models of short-term synaptic plasticity. These results highlight the dynamic nature of synaptic transmission and the interplay between synaptic strength and firing rates in awake animals.