Inferior Olive HCN1 Channels Coordinate Synaptic Integration and Complex Spike Timing

Derek L.F Garden,Marlies Oostland,Marta Jelitai,Arianna Rinaldi,Ian Duguid,Matthew F Nolan

doi:10.1016/j.celrep.2018.01.069

Abstract

SummaryCerebellar climbing-fiber-mediated complex spikes originate from neurons in the inferior olive (IO), are critical for motor coordination, and are central to theories of cerebellar learning. Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels expressed by IO neurons have been considered as pacemaker currents important for oscillatory and resonant dynamics. Here, we demonstrate that in vitro, network actions of HCN1 channels enable bidirectional glutamatergic synaptic responses, while local actions of HCN1 channels determine the timing and waveform of synaptically driven action potentials. These roles are distinct from, and may complement, proposed pacemaker functions of HCN channels. We find that in behaving animals HCN1 channels reduce variability in the timing of cerebellar complex spikes, which serve as a readout of IO spiking. Our results suggest that spatially distributed actions of HCN1 channels enable the IO to implement network-wide rules for synaptic integration that modulate the timing of cerebellar climbing fiber signals.

Highlights

Theories of motor learning propose critical roles for the timing of cerebellar complex spikes, which originate from neurons in the inferior olive (IO) (Albus, 1970; De Zeeuw et al, 2011; Marr, 1969)
We found that perfusion of ZD7288 hyperpolarized IO neurons by $30 mV (p = 5.08 3 10À5, n = 5, paired t test) (Figure 1C and 1D)
Because deletion or block of HCN1 channels causes a large hyperpolarization of the resting membrane potential of IO neurons, and because this might be expected to modify the driving force for synaptic currents and gating of other voltage-gated ion channels, we investigated whether the waveform of synaptic responses differed when compared at similar membrane potentials (Figures 2B and 2C)

Summary

Introduction

Theories of motor learning propose critical roles for the timing of cerebellar complex spikes, which originate from neurons in the inferior olive (IO) (Albus, 1970; De Zeeuw et al, 2011; Marr, 1969). Gap-junction-mediated electrical synaptic connections between IO neurons synchronize oscillatory activity (Bal and McCormick, 1997; De Zeeuw et al, 1998; Llinas et al, 1974; Long et al, 2002) and have been proposed to coordinate synaptic integration (Kistler and De Zeeuw, 2005). These distinctive excitable properties have motivated suggestions that the IO has unique computational roles within the brain (De Zeeuw et al, 1998; Welsh and Llinas, 1997). The extent to which intrinsic excitability of IO neurons influences spike timing in behaving animals is unclear

Results

Discussion

Conclusion