What optogenetic stimulation is telling us (and failing to tell us) about fast neurotransmitters and neuromodulators in brain circuits for wake-sleep regulation

Abstract

In the last eight years optogenetic tools have been widely used to identify functional synaptic connectivity between specific neuronal populations. Most of our knowledge comes from the photo-activation of channelrhodopsin-2 (ChR2) expressing inputs that release glutamate and GABA. More recent studies have been reporting releases of acetylcholine and biogenic amines but direct evidence for photo-evoked released of neuropeptides is still limited particularly in brain slice studies. The high fidelity in the responses with photo-evoked amino-acid transmission is ideal for ChR2-assisted circuit mapping and this approach has been successfully used in different fields of neuroscience. Conversely, neuropeptides employ a slow mode of communication and might require higher frequency and prolonged stimulations to be released. These factors may have contributed to the apparent lack of success for optogenetic release of neuropeptides. In addition, once released, neuropeptides often act on multiple sites and at various distances from the site of release resulting in a greater complexity of postsynaptic responses. Here, we focus on what optogenetics is telling us-and failing to tell us-about fast neurotransmitters and neuropeptides.

Figure 1. Comparison of optogenetic releases of amino-acid neurotransmitters and neuropeptides

Photostimulation at low frequency of ChR2 expressing axons/terminals releases only amino-acid neurotransmitters (left) but a higher frequency and prolonged photostimulation evokes release of both amino-acid and neuropeptides (right). Fast acting amino-acid transmitters activate ionotropic receptors on the postsynaptic neurons (1). Neuropeptides act slowly to activate postsynaptic G-protein-coupled receptors (GPCRs) on the postsynaptic neurons (2), on synaptic terminals to modulate synaptic activity (3, homosynaptic and 4, heterosynaptic modulations) and they can diffuse from the release site to act on distant postsynaptic targets (5). Neuropeptides can also be released from somato-dendritic varicosites and they can act as retrograde signals (6).