Cerebellum. 2025 Jul 21;24(5):135. doi: 10.1007/s12311-025-01892-1.
ABSTRACT
The α2-adrenergic receptor (α2-AR) is involved in various forms of information transmission in the cerebellar cortex, but its role in modulating sensory stimulation-induced synaptic plasticity remains unclear. We investigated the role of the α2-AR in facial stimulation-evoked long-term synaptic plasticity within molecular layer interneuron-Purkinje cell (MLI-PC) circuitry in the cerebellum by electrophysiological, pharmacological and immunohistochemical methods, and used alongside the rotarod test to assess the impact of receptor activity on motor learning in mice. Facial stimulation at 1 Hz induced MLI-PC long-term depression (LTD), which was significantly enhanced by microinjection of noradrenaline (NA) into the cerebellar molecular layer. Blockade of the NMDA receptor abolished facial stimulation-induced MLI-PC LTD; However, the effect could be triggered in the absence of NMDA activity through NA or UK14304 α2-AR activation with concurrent stimulation. In the absence of NMDA receptor activity, α2-AR-mediated facial stimulation-induced MLI-PC LTD was abolished by blockade of α2A-, but not α2B- or α2C-ARs. Facial stimulation-induced MLI-PC LTD was triggered by a selective α2A-AR agonist, guanfacine, but it was completely prevented by inhibition of protein kinase A (PKA) activity with KT5720. The rotarod test indicated that microinjection of guanfacine into the cerebellar cortex to activate α2A-ARs significantly improved early motor learning. Immunochemistry revealed α2A-AR immunoreactivity throughout the mouse cerebellar cortex, mostly in the PC layer and MLIs. These results suggest that NA facilitates facial stimulation-induced, α2A-AR/PKA signaling cascade-dependent MLI-PC LTD and promotes the acquisition of motor learning in mice.
PMID:40690091 | DOI:10.1007/s12311-025-01892-1
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