Multi-scale modelling of the cellular and molecular mechanisms of hyperpolarisation mediated synaptic plasticity in the vestibular nuclei

Abstract

Synaptic plasticity is assumed to underlie various forms of learning and memory. The classical theory believes that high-frequency presynaptic stimulation will induce long-term potentiation and low-frequency presynaptic stimulation will induce long-term depression, which are two forms of synaptic plasticity. Recently, for the first time, postsynaptic hyperpolarisation gated bidirectional plasticity was demonstrated in vestibular nerve synapses in the vestibular nucleus. In this system, the inhibitory Purkinje cells in the cerebellum can regulate the strength of excitatory neurotransmission in the vestibular nucleus neurons that they project to. This new type of plasticity is fully compatible with the proposed mechanism underlying motor learning during adaptation of the vestibulo-ocular reflex and can enhance our understanding of other forms of motor learning. However, the mechanistic cellular and molecular mechanisms behind this novel form of plasticity remain unknown. Here, I present a multi-scale model of hyperpolarisation mediated synaptic plasticity. This combines an electrical model of medial vestibular nucleus type B neurons in the vestibulo-ocular reflex system and comprehensive biochemical model of signalling pathway that underlies synaptic plasticity. In my model, I uncovered a complex relationship between Ca2+ concentration and synaptic strength. Then I found that presynaptic stimulation paired with hyperpolarisation can induce large amount of Ca2+ influx through low-voltage activated calcium channels, resulting in potentiation, and presynaptic stimulation without hyperpolarisation induce small amount of Ca2+ influx, resulting in depression. My finding reveals the cellular and molecular mechanisms underlying this novel plasticity and deepens our mechanistic understanding of motor learning.