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The molecular organization of cerebellar long-term depression

Key Points

  • The elements of complex signal-transduction processes that underlie long-term depression (LTD) — a unique form of synaptic plasticity displayed by cerebellar Purkinje cells — can be described as mediators and modulators, coincidence detectors and self-regenerating elements.

  • LTD is induced by the conjunctive stimulation of a bundle of parallel fibres (PFs) and a single climbing fibre (CF) that converge onto the same Purkinje cell, and is manifested as a persistent depression in transmission from the PF bundle to the Purkinje cell. Various reduced forms of LTD are also induced by introducing intermediate stages of the signal transduction that normally follows CF or PF stimulation.

  • More than 30 molecules are involved in LTD induction. Inhibition or genetic ablation of any of these molecules might block the induction of LTD. They include first messengers (glutamate, nitric oxide (NO), corticotropin-releasing factor (CRF) and insulin-like growth factor 1 (IGF1)), receptors (AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs), δ2 receptors, type 1 metabotropic glutamate receptors (mGluR1s), CRF receptors and IFG1 receptors), enzymes (guanylyl cylase, and phospholipase C and A2), Ca2+ and Na+ ions, second messengers (diacylglycerol, inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) and arachidonic acid), protein kinases (proteins kinase C (PKC) and protein kinase G, mitogen-activated protein kinase (MAPK), MAPK kinase and protein tyrosine kinase) and protein phosphatase 2A.

  • Mediators are essential for LTD induction, whereas modulators modify the actions of mediators. The NO–guanylyl cyclase pathway, which is required for LTD induction in cerebellar slices but not in tissue culture, is classified as a modulator. Receptors other than AMPARs at CF synapses are also considered to be modulators, because LTD can be induced even when they are bypassed by applying membrane depolarization that evokes Ca2+ influx.

  • PF AMPARs, PF mGluR1s and voltage-gated calcium channels (VGCCs) remain as candidate mediators. The associated Ca2+ and Na+ influxes, Ins(1,4,5)P3 receptors (InsP3Rs) and PKC are also considered to be mediators.

  • Coincidence detectors that supralinearly amplify the converging effects of PF and CF impulses are likely to be located at four sites: first, InsP3Rs, where PF-mGluR1-generated Ins(1,4,5)P3 and CF-activated VGCC-generated Ca2+ ions converge; second, VGCCs, where PF- and CF-induced membrane depolarizations converge; third, Ca2+ ions act on the phosphorylation–dephosphorylation (PD) system together with PF-mGluR1-derived Na+ ions and/or the activation of PKC; and fourth, phosphorylating action of the PD system on PF AMPARs might be enhanced if the PF transmitter (glutamate) sensitizes PF AMPARs for phosphorylation.

  • The final stage of LTD induction is the phosphorylation of PF AMPARs by the PD system, and their removal from the subsynaptic membrane by endocytosis. To explain the transition of PF AMPARs between the normal and depressed states, the PD system is postulated to contain a self-regenerating chemical circuit. A possible circuit is proposed, but its validity has yet to be examined.

Abstract

Synaptic plasticity is an important cellular mechanism for the formation of memory in neuronal circuits of the brain. Research during the past two decades has revealed surprisingly complex signal-transduction processes that underlie various forms of synaptic plasticity. More than 30 molecules are involved in the induction of long-term depression (LTD) — a unique form of synaptic plasticity in the cerebellum. Here, I review recent data on these molecules, defining their roles as mediators or modulators, coincidence detectors or components of a self-regenerating circuit, and show how they are organized to form an efficient molecular machinery for LTD induction.

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Figure 1: Basic neuronal circuit in the cerebellum.
Figure 2: Signal transduction after stimulation of a parallel fibre and a climbing fibre.
Figure 3: Simplified model of signal transduction.
Figure 4: Hypothetical structure of the PD system.

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DATABASES

LocusLink

δ2 receptors

AMPARs

amphiphysin

BDNF

CaMKII

CRF

CRFR1

dynamin

G-substrate

IGF1

IGF1R

InsP3Rs

JunB

Lyn

MAPK

MEK

mGluR1s

PKC

PKG

PLA2

PLC

PP1

PP2A

PP2B

PP2C

PP5

RyRs

VGCCs

FURTHER INFORMATION

Encyclopedia of Life Sciences

cerebellar plasticity

long-term depression and depotentiation

RIKEN Brain Science Institute

Glossary

PURKINJE CELLS

Inhibitory neurons in the cerebellum that use GABA as their neurotransmitter. Their cell bodies are situated beneath the molecular layer, and their dendrites branch extensively in this layer. Their axons project into the underlying white matter, and they provide the only output from the cerebellar cortex.

PARALLEL FIBRES

Parallel fibres are branches of the ascending axons of cerebellar granule cells. In the molecular layer of the cerebellar cortex, they run perpendicular to the planar Purkinje cell dendrites, with which they form so-called en passant synapses.

CLIMBING FIBRES

Cerebellar afferents that arise from the inferior olivary nucleus, each of which forms multiple synapses with a single Purkinje cell.

δ2 RECEPTOR

A subtype of glutamate receptor that is expressed selectively in Purkinje cells. δ2 receptors do not form functional glutamate-gated ion channels.

METABOTROPIC

A term that describes a receptor that is associated with G proteins and exerts its effects through enzyme activation.

IONOTROPIC

A term that describes a receptor that is associated with ion channels and generates electrical membrane currents.

RAS–RAF PATHWAY

Ras proteins are a group of small GTPases involved in growth, differentiation and cellular signalling that require the binding of GTP to enter into their active state. Raf is a serine/threonine kinase that is also implicated in cell proliferation, differentiation and survival. After its activation by Ras, Raf activates MEK and triggers the MAPK cascade.

MITOGEN-ACTIVATED PROTEIN KINASE CASCADE

A signalling cascade that relays signals from the plasma membrane to the nucleus. Mitogen-activated protein kinases (MAPKs), which represent the last step in the pathway, are activated by a wide range of proliferation- or differentiation-inducing signals. Extracellular-signal-regulated kinases (ERKs) are among the best-characterized MAPKs.

GRIP

Glutamate-receptor-interacting protein. A protein that can interact with AMPA receptors. It is thought to participate in regulating the spatial distribution and targeting of this receptor subtype.

PICK1

Protein that interacts with C-kinase 1. This protein also binds the carboxyl terminus of the GluR2 and GluR3 subunits of AMPA receptors.

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Ito, M. The molecular organization of cerebellar long-term depression. Nat Rev Neurosci 3, 896–902 (2002). https://doi.org/10.1038/nrn962

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