LTD has now been established as a synaptic plasticity specific to the cerebellum. Cellular and molecular mechanisms of LTD have been elucidated to some extent, but still a number of questions are left open. The most crucial question may concern its time course, as to how long the LTD lasts beyond the limit of the present maximum observation time of 3 hr, and whether and how it is eventually transformed to a permanent memory. Molecular mechanisms underlying LTD should be investigated further in respect to Ca2+ binding and storage, protein kinase C, phosphorylation of glutamate receptors, GTP proteins, etc. The ineffectiveness of mass field potentials in representing LTD makes such studies relatively difficult, and a hope for future development may be placed in reproduction of LTD in tissue cultured Purkinje cells or even in isolated glutamate receptors in a simplified form. The cerebellar neuronal network incorporating LTD as a memory element has been conceived as a simple perceptron-like (Albus 1971) or adaptive filter-like (Fujita 1982a) parallel processing computer. Such a neuronal computer incorporated in a reflex or a more complex movement system would endow the system with subtle capabilities of adaptation and learning. The scheme of the floccular control of the VOR closely resembles that of a self-tuning regulator, a type of adaptive control system. For cerebellar control of voluntary movements, however, another version of the adaptive control system, the model reference control system, seems to be more applicable (Ito 1986). This system continuously readjusts its dynamics by referring to errors derived through comparison of its performance with that of an internal model. It is important to note that a model for an unknown system can be built based on the same principle, by feeding errors derived from their comparison to adjust the model. It may thus be conceived that an internal model is built within the cerebellum in the manner of model reference adaptive control, and that an internal model so formed is utilized for adaptive control of movement. A recent simulation study successfully reproduced learning in formation of an arm trajectory based on these principles of model reference control (Kawato et al 1987). On the experimental side, however, the complex neural organization for control of locomotion, posture, and voluntary movements still eludes full elucidation. Nevertheless, evidence is accumulating to support the cerebellar learning hypothesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Long-term depression

1. In high decerebrate rabbits, cells were sampled extracellularly from the rostral flocculus. Purkinje cells were identified by their characteristic responses to stimulation of the contralateral inferior olive. Identification of basket cells was based on the absence of olivary responses and also on their location in the molecular layer adjacent to identified Purkinje cells. Mass field potentials in the flocculus were also studied.

2. Single pulse stimulation of a vestibular nerve, either ipsilateral or contralateral, at a rate of 2/sec excited Purkinje cells with a latency of 3-6 msec. This early excitation represents activation through vestibular mossy fibres, granule cells and their axons (parallel fibres). Similar early excitation also occurred in putative basket cells.

3. Conjunctive stimulation of a vestibular nerve at 20/sec and the inferior olive at 4/sec, for 25 sec per trial, effectively depressed the early excitation of Purkinje cells by that nerve, without an associated change in spontaneous discharge. The depression recovered in about ten minutes. This recovery was followed by the onset of a slow depression lasting for an hour.

4. Conjunctive vestibular—olivary stimulation produced no such depression in the following responses: early excitation in Purkinje cells induced from the vestibular nerve not involved in the conjunctive stimulation; early excitation in putative basket cells from either vestibular nerve; inhibition or rebound facilitation in Purkinje cells following the early excitation; vestibular-evoked field potentials in the granular layer and white matter of the flocculus. These observations lead to the conclusion that the depression occurs specifically at parallel fibre—Purkinje cell synapses involved in conjunctive stimulation.

5. Ionophoretic application of glutamate to Purkinje cells in conjunction with 4/sec olivary stimulation depressed the glutamate sensitivity of Purkinje cells; aspartate sensitivity was depressed to a much lesser degree. The depression diminished in about 10 min, but this recovery was succeeded by a slow depression lasting for an hour. The depression was seen only when glutamate sensitivity was relatively high, suggesting that the micro-electrode was impinging onto Purkinje cell dendrites. These observations suggest that subsynaptic chemosensitivity of Purkinje cells to the putative neurotransmitter of parallel fibres is involved in the depression observed after conjunctive stimulation of a vestibular nerve and the inferior olive.

6. The present results are consistent with the Marr-Albus assumption concerning plasticity of cerebellar neuronal networks.

Climbing fibre induced depression of both mossy fibre responsiveness and glutamate sensitivity of cerebellar Purkinje cells

Cerebellar Purkinje cells exhibit a unique type of synaptic plasticity, namely, long-term depression (LTD). When two inputs to a Purkinje cell, one from a climbing fiber and the other from a set of...

https://www.physiology.org/doi/pdf/10.1152/physrev.2001.81.3.1143

Cerebellar Long-Term Depression: Characterization, Signal Transduction, and Functional Roles

WHAT is the role of the cerebellum in motor coordination? Such coordination depends upon the integrity of the inferior olive, a major cerebellar afferent, as its lesion produces ataxic and dys-metric movement abnormalities1–2. Using multiple-microelectrode recordings, we report here that there are domains of Purkinje cell activity that are generated by olivary input during skilled tongue movements in rats. Such activity domains are highly rhythmic and time-locked to movement. Patterns of synchronous olivocerebellar activity are geometrically complex and can change during a sequence of movements. The results support the view that the inferior olive organizes movement in time, by entraining motor-neuronal firing through rhythmic activation of the cerebellum, and in space, by synchronously activating cell ensembles that allow the use of individual muscles. Dynamic repatterning of olivocerebellar synchrony may allow different combinations of muscles to be used for movements intended to have varying spatial structures.

Dynamic organization of motor control within the olivocerebellar system

The vestibulo-ocular reflex (VOR) is an elementary reflex, which attracted the attention of a number of classical neurophysiologists who studied, in particular, the reflexive compensatory eye movements induced by head movements (cfMagnus 1924, Lorente de No 1931). The major pathway for this reflex is the well-defined trineuronal are, composed of primary vestibu­ lar neurons, secondary vestibular neurons, and oculomotor neurons (Ra­ mon y Cajal 1909, Lorente de N6 1931, 1933, Szentagothai 1943, 1950, 1964, Brodal & Pompeiano 1957). The pioneering electrophysiological work by Lorente de N6 (1939) and by subsequent investigators recognized that the vestibulo-ocular reflex involves both excitation and inhibition (Szentllgothai 1950, Cohen et al 1964). More recent data about the VOR have been reviewed by Brodal (1974), Cohen (1974), Precht (1978), and Wilson & Melvill Jones (1979). In recent years, the vestibulo-ocular refiex has been reexamined in detail because of its close relationship with the cerebellum. Supported by remark­ able advances in cerebellar physiology and eye movement studies, the VOR has become an interesting and important subject of neurophysiology, espe­ cially for investigation of cerebellar control mechanisms. This article re­ views the efforts made in the past decade toward understanding the

Cerebellar Control of the Vestibulo-Ocular Reflex--Around the Flocculus Hypothesis

Histological evidence supporting the inferior olive as the major source of cerebellar climbing fibers in the rat

Effects of 3-acetylpyridine on the central nervous system of the rat, as demonstrated by silver methods

The olivocerebellar system. I. Delayed and slow inhibitory effects: An overlooked salient feature of cerebellar climbing fibers

The olivocerebellar system. II. Some ultrastructural correlates of inferior olive destruction in the rat.

The cerebellar molecular layer in adult rats has been studied with the electron microscope at several early and consecutive survival times following 3-acetylpyridine intoxication. Climbing fiber (CF) terminals underwent a fast process of electron-dense degeneration which became apparent from 16 hours onwards. A small proportion of degenerating terminals were depleted of vesicles and filled with a dark flocculent and granular homogeneous matrix. Microtubular changes in degenerating CF tendrils were observed. CF terminals were found in relation with every Purkinje cell in normal animals and completely disappeared within 72 hours after the treatment. CF synapses were found on Purkinje dendritic and somatic thorns, sometimes also on the dendritic shafts or even on the Purkinje soma. Convincing evidence of synaptic contacts of CF varicosities on either basket or stellate cells could not be obtained. CF synapses with Golgi II cell dendrites in the molecular layer were described. Decrease in the number of post-synaptic dendritic thorns normally assigned fo CF synapses was observed consequential to CF anterograde degeneration. The observations are consistent with previous conclusions drawn from light microscopic studies that the clearing up of CF debris in the molecular layer is completed within the short time of three days, and that the inferior olive seems to be the only source of CFs.

Early terminal degeneration of cerebellar climbing fibers after destruction of the inferior olive in the rat. Synaptic relationships in the molecular layer

Jean C. Desclin

Papers

Histological evidence supporting the inferior olive as the major source of cerebellar climbing fibers in the rat

Effects of 3-acetylpyridine on the central nervous system of the rat, as demonstrated by silver methods

The olivocerebellar system. I. Delayed and slow inhibitory effects: An overlooked salient feature of cerebellar climbing fibers

The olivocerebellar system. II. Some ultrastructural correlates of inferior olive destruction in the rat.

Early terminal degeneration of cerebellar climbing fibers after destruction of the inferior olive in the rat. Synaptic relationships in the molecular layer