SK2 channels in cerebellar Purkinje cells contribute to excitability modulation in motor-learning–specific memory traces

Grasselli, Giorgio; Boele, Henk Jan; Titley, Heather K.; Bradford, Nora; Beers, Lisa Van; Jay, Lindsey; Beekhof, Gerrit C.; Busch, Silas E.; Zeeuw, Chris I. De; Schonewille, Martijn; Hansel, Christian

doi:10.1371/journal.pbio.3000596

Cited by 61 publications

(53 citation statements)

References 84 publications

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“…Taken our results together, it would be expected that a decrease in the intrinsic excitability was induced in the cerebellar PC of the OKR learning group by an increase in the current threshold for generating AP. Our result supports the emerging hypothesis that cerebellar memory may be implemented not only by a change in synaptic transmission in the Purkinje cell, but also change in the intrinsic excitability [ 5 – 8 , 13 , 14 ]. Given that the intrinsic excitability of neurons is influenced by the conductance of various transmembrane ion channels that affect the passive and active membrane properties of the neuron, a further attempt should be made to determine the ion conductance that mediates the reduced excitability of cerebellar PCs after OKR learning.…”

Section: Main Textsupporting

confidence: 88%

Decreased intrinsic excitability of cerebellar Purkinje cells following optokinetic learning in mice

Kim

2020

Mol Brain

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The optokinetic response (OKR), a reflexive eye movement evoked by a motion of the visual field, is known to adapt its strength to cope with an environmental change throughout life, which is a type of cerebellum-dependent learning. Previous studies suggested that OKR learning induces changes in in-vivo spiking activity and synaptic transmission of the cerebellar Purkinje cell (PC). Despite the recent emphasis on the importance of the intrinsic excitability related to learning and memory, the direct correlation between the intrinsic excitability of PCs and OKR learning has not been tested. In the present study, by utilizing the whole-cell patch-clamp recording, we compared the responses of cerebellar PCs to somatic current injection between the control and learned groups. We found that the neurons from the learned group showed a significant reduction in mean firing rate compared with neurons in the control group. In the analysis of single action potential (AP), we revealed that the rheobase current for the generation of single AP was increased by OKR learning, while AP threshold, AP amplitude, and afterhyperpolarization amplitude were not altered. Taken together, our result suggests that the decrease in the intrinsic excitability was induced in the cerebellar PC of learned group by an increase in the current threshold for generating AP.

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Section: Main Textsupporting

confidence: 88%

Decreased intrinsic excitability of cerebellar Purkinje cells following optokinetic learning in mice

Kim

2020

Mol Brain

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“…In PCs, the main K + current is high-threshold activated ( Martina et al, 2003 ; Zang et al, 2018 ); therefore, depolarization-facilitated Na + currents dominate, causing larger normalized PRCs at high rates ( Figure 2 ). This facilitation may be further boosted in PCs by enhanced excitability, such as SK2 down-regulation reducing the AHP and elevating subthreshold membrane potentials ( Grasselli et al, 2020 ; Ohtsuki and Hansel, 2018 ). We did not explore possible PRC differences between zebrin-positive and zebrin-negative PCs due to a lack of data ( Zhou et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Firing rate-dependent phase responses of Purkinje cells support transient oscillations

Zang

Hong

Schutter

2020

eLife

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Both spike rate and timing can transmit information in the brain. Phase response curves (PRCs) quantify how a neuron transforms input to output by spike timing. PRCs exhibit strong firing-rate adaptation, but its mechanism and relevance for network output are poorly understood. Using our Purkinje cell (PC) model, we demonstrate that the rate adaptation is caused by rate-dependent subthreshold membrane potentials efficiently regulating the activation of Na+ channels. Then, we use a realistic PC network model to examine how rate-dependent responses synchronize spikes in the scenario of reciprocal inhibition-caused high-frequency oscillations. The changes in PRC cause oscillations and spike correlations only at high firing rates. The causal role of the PRC is confirmed using a simpler coupled oscillator network model. This mechanism enables transient oscillations between fast-spiking neurons that thereby form PC assemblies. Our work demonstrates that rate adaptation of PRCs can spatio-temporally organize the PC input to cerebellar nuclei.

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“…Several previous studies investigated PF→PC synaptic function and plasticity in cerebellum-dependent motor learning (Galliano et al, 2013; Grasselli et al, 2020; Gutierrez-Castellanos et al, 2017; Peter et al, 2020; Wada et al, 2007). Afferent sensory information to the cerebellar cortex is first processed at the upstream MF→GC synapse (Billings et al, 2014; Cayco-Gajic et al, 2017), which may contribute to cerebellar learning.…”

Section: Discussionmentioning

confidence: 99%

GluA4 enables associative memory formation by facilitating cerebellar expansion coding

Kita

Albergaria

Machado

et al. 2020

Preprint

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AMPA receptors (AMPARs) mediate excitatory neurotransmission in the CNS and their subunit composition determines synaptic efficacy. Whereas AMPAR subunits GluA1–GluA3 have been linked to particular forms of synaptic plasticity and learning, the functional role of GluA4 remains elusive. Here we used electrophysiological, computational and behavioral approaches to demonstrate a crucial function of GluA4 for synaptic excitation and associative memory formation in the cerebellum. Notably, GluA4-knockout mice had ∼80% reduced mossy fiber to granule cell synaptic transmission. The fidelity of granule cell spike output was markedly decreased despite attenuated tonic inhibition and increased NMDA receptor-mediated transmission. Computational modeling revealed that GluA4 facilitates pattern separation that is important for associative learning. On a behavioral level, while locomotor coordination was generally spared, GluA4-knockout mice failed to form associative memories during delay eyeblink conditioning. These results demonstrate an essential role for GluA4-containing AMPARs in cerebellar information processing and associative learning.

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SK2 channels in cerebellar Purkinje cells contribute to excitability modulation in motor-learning–specific memory traces

Cited by 61 publications

References 84 publications

Decreased intrinsic excitability of cerebellar Purkinje cells following optokinetic learning in mice

Decreased intrinsic excitability of cerebellar Purkinje cells following optokinetic learning in mice

Firing rate-dependent phase responses of Purkinje cells support transient oscillations

GluA4 enables associative memory formation by facilitating cerebellar expansion coding

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