Inferior Olive HCN1 Channels Coordinate Synaptic Integration and Complex Spike Timing

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.

How inhibitory and excitatory inputs gate output of the inferior olive

“…By contrast, subthreshold excitatory synaptic responses following MDJ stimulation evoke smaller amplitude changes, weaker phase resetting and a higher intertrial phase jitter of the STOs. In line with previous studies (Leznik et al, 2002; Best and Regehr, 2009; Bazzigaluppi et al, 2012a and 2012b; Lefler et al, 2014; Turecek et al, 2014 and 2016; Garden et al, 2017 and 2018) we show that stimulation of either CN or MDJ afferents in vitro elicits transient STOs in a subset of non-oscillating neurons with the hyperpolarizing component of the synaptic response directly affecting the phase and amplitude of such induced oscillations. These findings may well also hold in intact animals, since cell-attached and whole cell recordings of inferior olivary neurons in vivo (Chorev et al, 2007; Khosrovani et al, 2007; Van Der Giessen et al, 2008) as well as multiple single unit recordings of complex spike activity of ensembles of Purkinje cells in awake behaving animals (Negrello et al, 2019) indicate that a significant fraction of ‘silent’ olivary neurons can start to oscillate ‘conditionally’, dependent on peripheral input.…”

“…Olivary synaptic responses to excitatory input from the MDJ are comprised of a depolarization (V dep ) mediated by AMPA and NMDA receptors (Mathy et al, 2014; Turecek et al, 2014), followed by a hyperpolarization (V hyp ), mediated by both I h and SK channels (Garden et al, 2017; Garden et al, 2018). If sufficiently large, this hyperpolarization also drives a rebound depolarization (V reb ) mediated by I h and T-type calcium channels, which can reach threshold to initiate a spike.…”

Neural instructive signals for associative cerebellar learning

“…It is well known that expression of ChR2 and other membrane proteins can alter neuronal morphology and physiology [68][69][70] in ways that are still not fully understood. It is possible that IO neurons may be particularly vulnerable, for example due to their high levels of electrical coupling 53,71 . It is also possible that the use of the CaMKIIa promoter contributed in this case, either by driving particularly strong expression levels 70 or through perturbing endogenous CaMKII function in the IO 72 .…”

An axon-specific expression of HCN channels catalyzes fast action potential signaling in GABAergic interneurons

“…Activation of HCN channels creates a depolarizing influence that brings the RMP closer to the AP threshold, but the same HCN channels also generate a shunting conductance that reduces the input resistance and neuronal excitability 40 . Furthermore, the depolarization produced by HCN channels modulates functional states of Na + , K + , and Ca 2+ channels that are critical for AP signaling 37,[41][42][43][44] . These multiple actions of HCN channels make it challenging to predict the net effect of HCN channels on neuronal excitability in a cell type-specific manner.…”