RT Journal Article
SR Electronic
T1 A multi-scale model reveals cellular and physiological mechanisms underlying hyperpolarisation-gated synaptic plasticity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 418228
DO 10.1101/418228
A1 Yubin Xie
A1 Marcel Kazmierczyk
A1 Bruce P. Graham
A1 Mayank B. Dutia
A1 Melanie I. Stefan
A1 Mayank B. Dutia
YR 2019
UL http://biorxiv.org/content/early/2019/01/23/418228.abstract
AB Neurons in the medial vestibular nucleus (MVN) display hyperpolarisation-gated synaptic plasticity, where inhibition believed to come from cerebellar cortical Purkinje cells can induce long-term potentiation (LTP) or long-term depression (LTD) of vestibular nerve afferent synapses. This phenomenon is thought to underlie the plasticity of the vestibulo-ocular reflex (VOR). The molecular and cellular mechanisms involved are largely unknown. Here we present a novel multi-scale computational model, which captures both electrophysiological and biochemical signalling at vestibular nerve synapses on proximal dendrites of the MVN neuron. We show that AMPA receptor phosphorylation at the vestibular synapse depends in complex ways on dendritic calcium influx, which is in turn shaped by patterns of post-synaptic hyperpolarisation and vestibular nerve stimulation. Hyperpolarisation-gated synaptic plasticity critically depends on the activation of LVA calcium channels and on the interplay between CaMKII and PP2B in dendrites of the post-synaptic MVN cell. The extent and direction of synaptic plasticity depend on the strength and duration of hyperpolarisation, and on the relative timing of hyperpolarisation and vestibular nerve stimulation. The multi-scale model thus enables us to explore in detail the interactions between electrophysiological activation and post-synaptic biochemical reaction systems. More generally, this model has the potential to address a wide range of questions about neural signal integration, post-synaptic biochemical reaction systems and plasticity.