Circuit-specific remodeling of synaptic co-transmission in stress-responsive networks

Neurons do not always use a ‘one neurotransmitter-one receptor’ paradigm to communicate at synapses. Some neurons communicate using more than one neurotransmitter, a phenomenon termed co-transmission. Co-transmission can occur through a few distinct organizational modes at synapses, enabling the integration of excitatory, inhibitory, and modulatory signals in various combinations. Increasingly, evidence suggests that these organizational modes are particularly important in neural circuits functioning in stress response. In monoaminergic nuclei, the lateral habenula, and the hippocampus, stress exposure induces shifts in co-transmission via circuit-specific changes to neurotransmitter balance. Here, we review recent advances in our understanding of co-transmission in these circuits, with an emphasis on evidence that distinct modes of small-molecule co-transmission are employed in circuits that contribute to some of the multidimensional aspects of stress. We further discuss potential mechanisms that may recalibrate multi-transmitter signaling during stress-stimulated co-transmission. Currently, evidence suggests that stress affects not only single-transmitter systems but also multi-transmitter communication across neural circuits. Viewing co-transmission as a dynamic substrate of stress-induced neural plasticity, this review provides new insight into the neural basis of adaptive and maladaptive stress responses and may help identify novel therapeutic opportunities for affective disorders, such as major depressive disorder and bipolar disorder.