Gating of Long-Term Potentiation by Nicotinic Acetylcholine Receptors at the Cerebellum Input Stage

Francesca Prestori,Paola Lombardo,Maria Egle De Stefano,Daniel Bertrand,Egidio D’Angelo,Rianne Goselink,Daniela Gandolfi,Martijn Schonewille,Jonathan Mapelli,Lisa Mapelli,Claudia Bonardi,Chris De Zeeuw

doi:10.1371/journal.pone.0064828

Abstract

The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the α7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective α7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of α7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, α7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation.

Highlights

Long-term potentiation and depression (LTP and LTD) are forms of synaptic plasticity thought to constitute the biological basis of learning and memory in the brain [1]
Marr originally predicted that LTP at mossy fibre-granule cell synapses, if uncontrolled, would saturate synaptic capacity, impairing cerebellar functioning [6,8] and this form of plasticity was not considered in subsequent theoretical models [9]
The fact that MLA prevented the effect of nicotine and that desensitisation took minutes to become established indicated that nicotine concentration at the synapse was below 1 mM, implying that nicotine was acting through receptor activation rather than desensitisation

Summary

Introduction

Long-term potentiation and depression (LTP and LTD) are forms of synaptic plasticity thought to constitute the biological basis of learning and memory in the brain [1]. LTP and LTD are thought to be distributed in highly specific patterns in neural circuits and indiscriminate induction of these forms plasticity can saturate synaptic capacity, corrupting memory patterns [4]. Signals entering the granular layer through the mossy fibres can generate LTP and LTD [5,6,7], but the mossy fibre-granule cell relay does not appear to have specific monitoring systems capable of controlling plasticity. Marr originally predicted that LTP at mossy fibre-granule cell synapses, if uncontrolled, would saturate synaptic capacity, impairing cerebellar functioning [6,8] and this form of plasticity was not considered in subsequent theoretical models [9]. It has recently been suggested that gating mechanisms controlled by neuromodulators could hold the key to LTP regulation and LTD induction in the cerebellum granular layer, improving cerebellar adaptive control [3,10]

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Discussion

Conclusion