Cellular mechanisms of long-term depression in the cerebellum

Abstract

Long-term depression (LTD) of synaptic transmission at parallel fibre-Purkinje cell synapses is thought to be a cellular substrate of motor learning in the cerebellum. This use-dependent change in synaptic efficacy is induced by conjunctive stimulation of Parallel fibres and climbing fibres. Researchers agree that the induction of LTD requires, as an initial step, a calcium influx via voltage-gated Ca²⁺ channels into a Purkinje cell, together with activation of ionotropic (AMPA) and probably metabotropic subtypes of glutamate receptors of this cell. Indeed, due to the lack of specific antagonist, the final demonstration of the contribution of metabotropic receptors in the LTD induction process, under functional conditions, remains unanswered. The debate is now focused on the second-messenger processes leading to LTD of synaptic transmission at parallel fibre-Purkinje cell synapses, after the calcium influx into the cell. All researchers agree that a calcium-dependent cascade of events including activation of protein kinase C is necessary for LTD induction. In contrast, the recruitment in the LTD induction of another cascade, also triggered by Ca²⁺, that is, through synthesis of nitric oxide and cyclic GMP, remains controversial.

On the other hand, growing evidence suggests that these chains of reaction underlying LTD might ultimately lead to a genuine change in the functional characteristics of AMPA receptors at the parallel fibre-Purkinje cell synapses.