Long-term Potentiation of Inhibitory Synaptic Transmission onto Cerebellar Purkinje Neurons Contributes to Adaptation of Vestibulo-Ocular Reflex

Abstract

Synaptic plasticity in the cerebellum is thought to contribute to motor learning. In particular, long-term depression (LTD) at parallel fiber (PF) to Purkinje neuron (PN) excitatory synapses has attracted much attention of neuroscientists as a primary cellular mechanism for motor learning. In contrast, roles of plasticity at cerebellar inhibitory synapses in vivo remain unknown. Here, we have investigated the roles of long-lasting enhancement of transmission at GABAergic synapses on a PN that is known as rebound potentiation (RP). Previous studies demonstrated that binding of GABA A receptor with GABA A receptor-associated protein (GABARAP) is required for RP, and that a peptide that blocks this binding suppresses RP induction. To address the functional roles of RP, we generated transgenic mice that express this peptide fused to a fluorescent protein selectively in PNs using the PN-specific L7 promoter. These mice failed to show RP, although they showed no changes in the basal amplitude or frequency of miniature IPSCs. The transgenic mice also showed no abnormality in gross cerebellar morphology, LTD, or other excitatory synaptic properties, or intrinsic excitability of PNs. Next, we attempted to evaluate their motor control and learning ability by examining reflex eye movements. The basal dynamic properties of the vestibuloocular reflex and optokinetic response, and adaptation of the latter, were normal in the transgenic mice. In contrast, the transgenic mice showed defects in the adaptation of vestibulo-ocular reflex, a model paradigm of cerebellum-dependent motor learning. These results together suggest that RP contributes to a certain type of motor learning.

Motor Learning and the Cerebellum

“…These latter experiments indicate that LTD is not essential for vestibuloocular reflex adaptation, but they do not exclude the possibility that LTD contributes to this form of motor learning under physiological conditions. Possibly, the blockage of LTD expression at the parallel fiber to Purkinje cell synapse in the GluRd7 knockin, GluR2K882A knockin, and PICK1 knockout is compensated for by LTP at the parallel fiber to molecular layer interneuron synapse (Jörntell and Ekerot 2002;Gao et al 2012;Tanaka et al 2013). Even though motor learning in the zebrin-positive floccular zones may be dominated by postsynaptic and intrinsic potentiation of Purkinje cell activity, the olivocerebellar system is endowed with various distributed forms of plasticity that operate in a synergistic fashion and allow for ample compensation (Gao et al 2012).…”

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

“…Although the roles and regulatory neuronal pathways are similar between VOR and OKR, differential regulations of VOR and OKR by cerebellar synaptic plasticity mechanisms have been reported 8, 10, 11 . In addition, Faulstich et al .…”

Chronic imaging of movement-related Purkinje cell calcium activity in awake behaving mice

“…For example, LTD in PCs can affect conditioned eyeblink responses (Koekkoek et al 2003;Ohtani et al 2014; but see Welsh et al 2005), spatial learning (Burguiere et al 2005;Rochefort et al 2011), adaptation of the horizontal optokinetic reflex , and smooth pursuit eye movements (Medina and Lisberger 2008). However, climbing fiber-driven LTD alone has failed to fully account for behavioral learning in many cases including adaptation of the vestibuloocular reflex or conditioned eyeblink responses (Ke et al 2009;Kimpo et al 2014;Ly et al 2013;Schonewille et al 2010Schonewille et al , 2011Tanaka et al 2013;Wetmore et al 2014). In addition, the olivo-cerebellar system may play a more general role in organizing motor control through temporal pattern generation (Jacobson et al 2008).…”