Inferior Olive HCN1 Channels Coordinate Synaptic Integration and Complex Spike Timing

• Published in: Cell reports (Cambridge) 2018-02, Vol.22 (7), p.1722-1733
• Main Authors: Garden, Derek L.F., Oostland, Marlies, Jelitai, Marta, Rinaldi, Arianna, Duguid, Ian, Nolan, Matthew F.
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Animals; Calcium Channels - metabolism; cerebellum; Cerebellum - cytology; excitability; gap junction; Gap Junctions - metabolism; Gene Deletion; Glutamic Acid - metabolism; hyperpolarization-activated current; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism; inferior olive; ion channel; Male; Mice, Inbred C57BL; Movement; movement coordination; neural code; Neurons - metabolism; oscillation; Synapses - metabolism; synaptic integration; Time Factors; Wakefulness
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.01.069

Cerebellar 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. [Display omitted] •HCN1 channels in IO neurons control synaptic response and spiking activity•Network actions of HCN1 channels enable bidirectional synaptic responses•Local actions of HCN1 channels control spike timing and spikelet number•In awake mice, HCN1 channels reduce timing variability of cerebellar complex spikes Garden et al. show that in the IO, distinct network-wide and local actions of HCN1 channels, respectively, determine the waveform of synaptic potentials and timing of spike initiation. Thus, spatially distributed actions of HCN1 signaling may support roles of the IO in motor coordination.