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

Abstract

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

Novel Scaffold Agonists of the α2A Adrenergic Receptor Identified via Ensemble-Based Strategy

“…Previous studies have shown that activation of α 2A -ARs can inhibit adenylate cyclase activity to exert physiological effects through the PKA signaling pathway [ 16 , 17 ]. The catalytic domain of PKA, labeled with enhanced green fluorescent protein (PKAcat-EGFP), is typically localized in highly fluorescent aggregates in the cytoplasm for unstimulated cells [ 18 ].…”

Acute stress facilitates glutamatergic long-term potentiation in PVN magnocellular neurons through beta-adrenergic receptor/PKA cascade in vitro in rats

“…In cerebellar cortex, activation of β-AR by a speci c agonist or NE did not directly alter parallel ber-Purkinje cell synaptic transmission, but lowered the threshold for longterm depression induction at parallel ber-Purkinje cell synapses in the occulus through PKA signaling pathway [37]. Under in vivo conditions, NE depresses spontaneous complex spikes activity and the facial stimulation evoked molecular interneuron-Purkinje cell synaptic transmission via AR/PKA signaling pathway in vivo in mice [38,39]. In addition, activation of α-and β-ARs modulated the strength of synaptic transmission and long-term plasticity via cAMP /PKA signaling pathway in the brain [37,[40][41][42][43].…”