Two Forms of Synaptic Depression Produced by Differential Neuromodulation of Presynaptic Calcium Channels

Neuromodulators are important regulators of synaptic transmission throughout the brain. At the presynaptic terminal, neuromodulation of calcium channels (CaVs) can affect transmission not only by changing neurotransmitter release probability, but also by shaping short-term plasticity (STP). Indeed, changes in STP are often considered a requirement for defining a presynaptic site of action. Nevertheless, some synapses exhibit non-canonical forms of neuromodulation, where release probability is altered without a corresponding change in STP. Here, we identify biophysical mechanisms whereby both canonical and non-canonical presynaptic neuromodulation can occur at the same synapse. At a subset of glutamatergic terminals in prefrontal cortex, GABAB and D1/D5 dopamine receptors suppress release probability with and without canonical increases in short-term facilitation by modulating different aspects of presynaptic CaV function. These findings establish a framework whereby signaling from multiple neuromodulators can converge on presynaptic CaVs to differentially tune release dynamics at the same synapse. [Display omitted] •Dopamine suppresses specific glutamatergic inputs to prefrontal cortex•This presynaptic suppression occurs without increasing short-term facilitation•GABAB receptors increase facilitation at the same synapse•Biased regulation of presynaptic calcium channels underlies these differences Presynaptic neuromodulators like GABAB receptors impose high-pass filters on synaptic transmission, facilitating release when inputs arrive at high frequency. Burke et al. show that, unlike GABAB, dopamine suppresses glutamatergic release in prefrontal cortex independent of frequency, thus regulating synaptic gain.