Noradrenaline depresses facial stimulation-evoked cerebellar MLI-PC synaptic transmission via α2-AR/PKA signaling cascade in vivo in mice

The noradrenergic fibers of locus coeruleus (LC) together with mossy fibers and climbing fibers comprise the three types of cerebellar afferents, which modulate cerebellar neuronal circuit function via adrenergic receptors (ARs). We previously demonstrated that noradrenaline (NA) modulated synaptic transmission in mouse cerebellar cortex. In the present study, we investigated the effect of NA on the facial stimulation-evoked cerebellar molecular layer interneuron (MLI)-Purkinje cell (PC) synaptic transmission in urethane-anesthetized mice using in vivo cell-attached recording technique and pharmacological method. The MLI-PC synaptic transmission was induced by air-puff stimulation (duration: 60 ms) of ipsilateral whisker pad, which exhibited negative components (P1 and P2) accompanied with a pause of simple spike (SS). Cerebellar molecular layer application of NA (15 µM) decreased the amplitude and area under the curve (AUC) of P1, and the pause of SS, but increased the P2/P1 ratio. The NA-induced decrease in P1 amplitude was concentration-dependent, and the half inhibitory concentration (IC 50 ) was 10.94 µM. The NA-induced depression of the facial stimulation-evoked MLI-PC GABAergic synaptic transmission was completely abolished by blockade of α-ARs or α2-AR, but not by antagonist of α1-AR or β-AR. Bath application of α2-AR agonist inhibited the MLI-PC synaptic transmission, as well as occluded the effect of NA on the synaptic response. NA-induced depression of the MLI-PC synaptic transmission was completely blocked by a mixture of α2A- and 2B-AR antagonists, as well as abolished by inhibition of protein kinase A (PKA). In addition, electrical stimulation of molecular layer evoked MLI-PC GABAergic synaptic transmission in the presence of AMPA receptor antagonist, which was inhibited by NA through α2-AR. Our results indicate that NA inhibits MLI–PC GABAergic synaptic transmission via an α2-AR/PKA signaling pathway, at least in part through a presynaptic mechanism. These results suggest that the adrenergic neurons in the LC may modulate the output of PCs through regulating MLI–PC synaptic transmission in sensory information transmission of mouse cerebellar cortex.