Inhibition gates supralinear Ca2+ signaling in Purkinje cell dendrites during practiced movements

Abstract

Motor learning involves neural circuit modifications in the cerebellar cortex, likely through re-weighting of parallel fiber inputs onto Purkinje cells (PCs). Climbing fibers instruct these synaptic modifications when they excite PCs in conjunction with parallel fiber activity, a pairing that enhances climbing fiber-evoked Ca2+ signaling in PC dendrites. In vivo, climbing fibers spike continuously, including during movements when parallel fibers are simultaneously conveying sensorimotor information to PCs. Whether parallel fiber activity enhances climbing fiber Ca2+ signaling during motor behaviors is unknown. In mice, we found that inhibitory molecular layer interneurons (MLIs), activated by parallel fibers during practiced movements, suppressed parallel fiber enhancement of climbing fiber Ca2+ signaling in PCs. Similar results were obtained in acute slices for brief parallel fiber stimuli. Interestingly, more prolonged parallel fiber excitation revealed latent supralinear Ca2+ signaling. Therefore, the balance of parallel fiber and MLI input onto PCs regulates concomitant climbing fiber Ca2+ signaling.

Molecular layer interneurons in the cerebellum encode for valence in associative learning

“…In addition, adaptive changes in the vestibulo-ocular reflex elicited by CF optogenetic activation switched from increase to decrease depending on whether MLIs were co-activated using optogenetics 18 . Finally, MLIs gate supralinear CF-evoked Ca2+ signaling in the PC dendrite 41 . These studies suggest that the valence of learning is graded by MLI activity.…”

Conversion of graded presynaptic climbing fiber activity into graded postsynaptic Ca2+ signals by Purkinje cell dendrites

“…First, MLIs appeared to be relatively inactive during quiescence suggesting that inhibition of CF-evoked dendritic Ca 2+ signaling in PCs (Callaway et al, 1995;Rowan et al, 2018) does not account for the reduced size of spontaneous events. In fact, in Crus II, chemogenetic disinhibition of the molecular layer has no effect on spontaneous Ca 2+ event amplitudes (Gaffield et al, 2018). Interestingly, we observed that MLIs in Crus I were coactivated with PCs in response to sensory cue presentation.…”

“…For analysis of Ca 2+ event size, we focused on discrete, isolated responses (Gaffield et al, 2018). Thus, we avoided potential uncertainties associated with GCaMP6f non-linearity (Chen et al, 2013) for overlapping events.…”

“…For example, the coincident activity of parallel fibers can produce an indirect, non-linear enhancement of CF-evoked responses, apart from direct Ca 2+ entry, by affecting PC dendritic excitability (Otsu et al, 2014;Wang et al, 2000). However, this non-linear enhancement is tightly regulated by feedforward inhibition (Gaffield et al, 2018), and any behavioral contexts that enable granule cells to influence CF-evoked responses have yet to be resolved. It is also possible that parallel fibers and/or MLIs have a subcellular influence on PC dendritic Ca 2+ signaling (Callaway et al, 1995;Roome and Kuhn, 2018), not apparent in the average, arbor-wide response.…”

The origin of physiological local mGluR1 supralinear Ca2+ signals in cerebellar Purkinje neurons

“…Episodes of hyp state can be due, in principle, to synaptic inhibition coactively occurring during activity patterns associated with cerebellar learning (Suvrathan and Raymond, 2018). Indeed, it was recently demonstrated that optogenetic activation of interneurons in the molecular layer strongly affects PF synaptic plasticity and motor learning, as well as CF-mediated signalling Gaffield et al, 2018). Another possibility is that hyp state episodes are intrinsically generated in PNs by a "priming" signal that hyperpolarises the cell, for instance by activating a K + conductance.…”