Norepinephrine Facilitates Induction of Long-term Depression through ß-Adrenergic Receptor at Parallel Fiber-to-Purkinje Cell Synapses in the Flocculus.

The cerebellum is involved in motor learning, and long-term depression (LTD) at parallel fiber-to-Purkinje cell (PF-PC) synapses has been considered to be a primary cellular mechanism for motor learning. In addition, the contribution of norepinephrine (NE) to cerebellum-dependent learning paradigms has been reported. Thus, the roles of LTD and of NE in motor learning have been studied separately, and the relationship between the effects of NE and LTD remains unclear. Here, we examined effects of ß-adrenergic receptor (ß-AR) activity on the synaptic transmission and LTD at PF-PC synapses in the cerebellar flocculus. The flocculus regulates adaptation of oculomotor reflexes, and we previously reported the involvement of both LTD and ß-AR in adaptation of an oculomotor reflex. Here we found that specific agonists for ß-AR or NE did not directly change synaptic transmission, but lowered the threshold for LTD induction at PF-PC synapses in the flocculus. In addition, protein kinase A (PKA), which is activated downstream of ß-AR, facilitated the LTD induction. Altogether, these results suggest that NE facilitates LTD induction at PF-PC synapses in the flocculus by activating PKA through ß-AR.

Occurrence of long-term depression in the cerebellar flocculus during adaptation of optokinetic response.

Long-term depression (LTD) at parallel fiber (PF) to Purkinje cell (PC) synapses has been considered as a main cellular mechanism for motor learning. However, the necessity of LTD for motor learning was challenged by demonstration of normal motor learning in the LTD-defective animals. Here, we addressed possible involvement of LTD in motor learning by examining whether LTD occurs during motor learning in the wild-type mice. As a model of motor learning, adaptation of optokinetic response (OKR) was used. OKR is a type of reflex eye movement to suppress blur of visual image during animal motion. OKR shows adaptive change during continuous optokinetic stimulation, which is regulated by the cerebellar flocculus. After OKR adaptation, amplitudes of quantal excitatory postsynaptic currents at PF-PC synapses were decreased, and induction of LTD was suppressed in the flocculus. These results suggest that LTD occurs at PF-PC synapses during OKR adaptation.

Differential regulations of vestibulo-ocular reflex and optokinetic response by ß- and α2-adrenergic receptors in the cerebellar flocculus.

Norepinephrine modulates synaptic plasticity in various brain regions and is implicated in memory formation, consolidation and retrieval. The cerebellum is involved in motor learning, and adaptations of the vestibulo-ocular reflex (VOR) and optokinetic response (OKR) have been studied as models of cerebellum-dependent motor learning. Previous studies showed the involvement of adrenergic systems in the regulation of VOR, OKR and cerebellar synaptic functions. Here, we show differential contributions of ß- and α2-adrenergic receptors in the mouse cerebellar flocculus to VOR and OKR control. Effects of application of ß- or α2-adrenergic agonist or antagonist into the flocculus suggest that the ß-adrenergic receptor activity maintains the VOR gain at high levels and contributes to adaptation of OKR, and that α2-adrenergic receptor counteracts the ß-receptor activity in VOR and OKR control. We also examined effects of norepinephrine application, and the results suggest that norepinephrine regulates VOR and OKR through ß-adrenergic receptor at low concentrations and through α2-receptor at high concentrations.