Long-Term Depression of Intrinsic Excitability Accompanied by Synaptic Depression in Cerebellar Purkinje Cells

Abstract

Long-term depression (LTD) at the parallel fiber (PF)-to-cerebellar Purkinje cell (PC) synapse is implicated in the output of PCs, the sole output of the cerebellar cortex. In addition to synaptic plasticity, intrinsic excitability is also one of the components that determines PC output. Although long-term potentiation of intrinsic excitability (LTP-IE) has been suggested, it has yet to be investigated how PF-PC LTD modifies intrinsic excitability of PCs. Here, we show that pairing of the PF and climbing fiber (CF) for PF-PC LTD induction evokes LTD-IE in cerebellar PCs from male C57BL/6 mice. Interestingly, this intrinsic plasticity showed different kinetics from synaptic plasticity, but both forms of plasticity share Ca 2ϩ signaling and protein kinase C pathway as their underlying mechanism. Although smallconductance Ca 2ϩ -activated K ϩ channels play important roles in LTP-IE, no direct implication has been found. After PF-PC LTD induction, neither the temporal summation of dendritic EPSP nor the power of spike frequency adaptation is changed, indicating that cerebellar LTD executes the information processing in a quantitative way without quality changes of synaptic integration and generation of output signals. Our results suggest that LTD-IE may have a synergistic effect with synaptic depression on the total net output of neurons by amplifying the modification of PF synaptic transmission.

Intrinsic plasticity of cerebellar Purkinje cells in motor learning circuits

“…Next, we examined the temporal alteration of PC excitability through ex vivo recordings after the learning task; at short-, mid- and long-term time periods. In agreement with the results of in vitro experiments (Shim et al, 2017; (Figure S3A), the firing frequency was decreased 1 hour after training in the wild-type littermates (Figure 3A). The AP firing frequency of PCs was measured in current clamp mode through the injection of brief current steps from the membrane potential of approximately −70 mV (500 ms, from +100 pA to +500 pA with an increment of 100 pA, step interval 4.5 s).…”

“…This suggests that the activity-dependent modulation of the output of PCs might derive adequate memory transduction from the cerebellar cortex to the VN. Interestingly, we previously verified that the excitability of PCs shows bi-directionality in response to the different patterns of synaptic plasticity induction (Shim et al, 2017) and postulated that the intrinsic plasticity of PCs plays a role in VOR learning, based on former results (Ryu et al, 2017).…”

Synaptic and intrinsic plasticity coordinate spike output in cerebellar Purkinje cells

“…In summary, our recordings from floccular PCs revealed that the postsynaptic spiking output reflects the synaptic plasticity by linking intrinsic plasticity. Since the intrinsic plasticity is modulated in the same polarity to the synaptic plasticity, the changes in the excitability has been assumed to amplify the changes in synaptic efficacy (Belmeguenai et al, 2010;Shim et al, 2017). In this work, we further elucidate the several physiological features of intrinsic plasticity in cerebellar PCs.…”

“…Emerging evidence has revealed that learning and memory is implemented not only by activitydependent synaptic plasticity but also by non-synaptic intrinsic plasticity in several neural circuits (Crestani et al, 2018;Lisman et al, 2018;Shim et al, 2018;Zhang and Linden, 2003). Of interest, intrinsic excitability contributes to integration of synaptic inputs and generation of net neuronal output (Hoffman et al, 1997;Lev-Ram et al, 2003, 1995Shim et al, 2017). Therefore, the plasticity of intrinsic excitability may incorporate synaptic plasticity, and thereby formation of postsynaptic spike output (Najac and Raman, 2015).…”

“…Cerebellar PC intrinsic plasticity has been implicated as a neural computational feature of the information processing of cerebellar cortex (Belmeguenai et al, 2010;Grassi and Pettorossi, 2001;Shim et al, 2018Shim et al, , 2017Steuber et al, 2007). 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).…”