Neuromodulators such as noradrenaline (NA) and serotonin (5-HT) affect intraneuronal levels of cyclic AMP (cAMP), but their exact downstream effects remain unclear. Patzke et al. showed that incubating excitatory human neurons (derived from pluripotent stem cells) with NA increased synaptic vesicle (SV) density, whereas incubation with 5-HT decreased SV density. These effects depended on the α2A-adrenergic receptor and the 5-HT7 receptor, which inhibit and promote the activity of the cAMP-dependent enzyme protein kinase A (PKA), respectively. PKA is known to phosphorylate the synaptic protein synapsin 1, and human-induced neurons lacking synapsin 1 showed reduced numbers of SVs. Thus, neuromodulators may differentially affect the activity of synapsin 1, which in turn regulates SV number.
Patzke, C. et al. Neuromodulator signalling bidirectionally controls vesicle numbers in human synapses. Cell 179, 498–513 (2019)