Intrinsic plasticity of cerebellar Purkinje cells in motor learning circuits

Abstract

19Intrinsic plasticity of cerebellar Purkinje cells (PCs) is recently highlighted in the cerebellar local circuits, however, 20 its physiological impact on the cerebellar learning and memory remains elusive. Using a mouse model of memory 21 consolidation deficiency, we found that the intrinsic plasticity of PCs may be involved in motor memory 22 consolidation. Gain-up training of the vestibulo-ocular reflex produced a decrease in the synaptic weight of PCs 23 in both the wild-type and knockout groups. However, intrinsic plasticity was impaired only in the knockout mice. 24Furthermore, the observed defects in the intrinsic plasticity of PCs led to the formation of improper neural 25 plasticity in the vestibular nucleus (VN) neurons. Our results suggest that the synergistic modulation of intrinsic 26 and synaptic plasticity in PCs is required for the changes in the local connectivity between the cerebellum and 27 VN that contribute to the long-term storage of motor memory. 55the impact of intrinsic plasticity within the motor learning circuits, we assessed neural activity in the VN 56 neurons following the gain-increase learning. Firing rate potentiation was gradually developed over time, 57 3 and excitatory synaptic transmission was also increased after learning. Notably, neither synaptic plasticity 58 nor intrinsic plasticity of the VN neurons was observed in STIM PKO mice. This implies that the subsequent 59 increases in the neural activity in the VN neurons may be derived from changes in the cortical output, as 60 determined by the intrinsic plasticity of the cerebellar PCs.61 62 Materials and Methods 63 64 Animal model 65 We crossed homozygous PCP2-Cre line (B6.129-Tg(Pcp2-cre)2Mpin/J line, Jackson Laboratory) with the 66 STIM1-floxed line (C57BL/6 background) to generate PC-specific STIM1 knockout line as our recent study (Ryu 67 et al., 2017). Only male mice were used in all experiments, and procedures were approved by the Institutional 68 69 Surgery 70All surgical procedure was similar to our previous paper (see Ryu et al., 2017). Surgery for head fixation has been 71 done at 7-to 8-weeks-old. Zoletil (Zoletil 50, Virbac, 15mg/kg) + xylazine (Rompun, Bayer, 15mg/kg) mixture 72 was applied to anesthetize mice through intraperitoneal injection. After surgery, 24 to 48 hours of recovery time 73 were given to mice. 74Behavior test 75The installation and most of procedure were similar to our previous paper (see Ryu et al., 2017). To control 76 pupil dilatation, physostigmine salicylate solution (Eserine; Sigma Aldrich) was treated with brief isoflurane 77 anesthetization, and at least 20mins were given to washout the side-effect of anesthetization. The concentration 78 of eserine solution was constantly increased from 0.1%, 0.15% and 0.2% because of drug resistance. Two sessions 79 of acclimation were performed. At first, the mouse was fixed onto a restrainer for 15 minutes and experienced 80 light on and off, several brief visual and vestibular stimulation for checking surgical failure. Secondly, calibration 81...

Synaptic and intrinsic plasticity coordinate spike output in cerebellar Purkinje cells

“…Next, we further tested if excitability changes per se would be reflected in spiking output. We used a transgenic mice model, the PC-specific stromal interaction molecule 1 knockout mice (STIM1 PKO ), previously reported the impairment of intrinsic plasticity without the deficit of synaptic plasticity (Jang et al, 2019;Ryu et al, 2017). Consistent with a previous study, the synaptic plasticity was comparable between genotypes but the STIM1 PKO exhibited a deficit of LTD-IE (figure 3G…”

“…Notably, bidirectional modulation of synaptic plasticity at the PF-PC synapses has been found to be accompanied by intrinsic plasticity, which shows the same polarity with synaptic plasticity, indicating that the intrinsic plasticity might synergistically enable the PC spike output to be sufficiently modulated when synaptic plasticity occurs (Belmeguenai et al, 2010;Shim et al, 2017). Furthermore, multiple lines of evidence have suggested that non-synaptic intrinsic plasticity of PCs might be another player involved in information storage for cerebellar motor learning (Jang et al, 2019;Ryu et al, 2017;Schonewille et al, 2011). However, how intrinsic plasticity contributes to inputoutput coordination in accordance with learning is still unclear.…”

Intrinsic Plasticity of Cerebellar Purkinje Cells Contributes to Motor Memory Consolidation

“…However, several studies have proposed that synaptic plasticity at the PF-PC synapse is not sufficient to explain VOR learning (Wulff et al, 2009;Schonewille et al, 2011;Ito, 2013). Emerging evidence suggests that neural plasticity at multiple sites, including the cerebellar cortex and vestibular nucleus (VN), is required for VOR learning (Boyden et al, 2004;Porrill and Dean, 2007;Clopath et al, 2014;Yamazaki et al, 2015;Jang et al, 2019). Furthermore, it has been suggested that VOR memory is formed in cerebellar cortical areas through PF-PC plasticity at the early phase of adaption; and at late phase, plasticity occurs in VN (Ito, 2013).…”

Research on the cerebellum yields rewards

“…There are several intriguing parallels between the signals found by Sendhilnathan and colleagues and the signals involved in cerebellar control of movement. First, as with reward-driven learning, for some motor skills, cerebellar Purkinje cells contribute selectively to new motor learning and not to performing older motor skills 15,16 . Second, Purkinje-cell activity carries information that could guide both ongoing behaviour and the induction of learning during motor-and reward-based learning 17 .…”