Genetic Activation of Locus Coeruleus Noradrenergic Neurons Modulates Cerebellar MF-GrC Synaptic Plasticity via...

Locus coeruleus (LC) noradrenergic neurons project their axons to the cerebellar cortex and modulate cerebellar circuit function via distinct adrenergic receptor (AR) subtypes. The present study investigated the mechanism by which optogenetic activation of LC noradrenergic neurons modulates facial stimulation-evoked long-term synaptic plasticity at cerebellar mossy fiber-granule cell (MF-GrC) synapses in urethane-anesthetized DBH-Cre mice. Blockade of GABA_A receptors, 20 Hz facial stimulation induced MF-GrC long-term potentiation (LTP) in the control group, and this LTP was impaired by optogenetic activation of LC noradrenergic neurons via α2-ARs. Meanwhile, facial stimulation induced LTP of glutamate sensor fluorescence in the granular layer, which was abolished by chemogenetic activation of LC noradrenergic neurons. Following NMDA receptor blockade, optogenetic activation of LC noradrenergic neurons triggered facial stimulation-induced MF-GrC long-term depression (LTD) via α2A-ARs. Optogenetically activated LC noradrenergic neuron-induced MF-GrC LTD was abolished by protein kinase A (PKA) inhibition but not by protein kinase C inhibition. Immunofluorescence results revealed abundant α2A-AR expression in the granular layer, with particularly high levels in glomeruli, and no colocalization with the glutamate sensor. These results indicate that optogenetic activation of LC noradrenergic neurons impairs facial stimulation-induced MF-GrC LTP by triggering presynaptic LTD via the α2A-AR/PKA signaling cascade.