Calcium is an intracellular mediator of the climbing fiber in induction of cerebellar long-term depression.

1. Using a rabbit cerebellar slice preparation, we stimulated a classical conditioning procedure by stimulating parallel fiber inputs to Purkinje cells with the use of a brief, high-frequency train of eight constant-current pulses 80 ms before climbing fiber inputs to the same Purkinje cell were stimulated with the use of a brief, lower frequency train of three constant-current pulses. In all experiments, we assessed the effects of stimulation by measuring the peak amplitude of Purkinje cell excitatory postsynaptic potentials (EPSPs) to single parallel fiber test pulses. 2. Intradendritically recorded Purkinje cell EPSPs underwent a long-term (> 20 min) reduction in peak amplitude (30%) after paired stimulation of the parallel and climbing fibers but not after unpaired or parallel fiber alone stimulation. We call this phenomenon pairing-specific long-term depression (PSD). 3. Facilitation of the peak amplitude of a second EPSP elicited by a parallel fiber train occurred both before and after paired stimulation suggesting that the locus of depression was not presynaptic. Depression of the peak amplitude of a depolarizing response to focal application of glutamate following pairings of parallel and climbing fiber stimulation added support to a suggested postsynaptic locus of the PSD effect. 4. The application of aniracetam potentiated EPSP peak amplitude by 40%, but these values returned to baseline as a result of pairings. With the removal of aniracetam from the bath 20 min after pairings, normal levels of pairing-specific EPSP depression were observed, indicating that the effect did not result from direct desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. 5. Incubation of slices in the protein kinase inhibitor H-7 potentiated EPSP peak amplitudes slightly (9%), but peak amplitudes returned to baseline levels after pairings. The net reduction in EPSP peak amplitude of < 10% after pairings suggested that H-7 partially blocked PSD and that, in turn, PSD involved protein kinases. 6. The means of induction and the specificity of those means suggest that the phenomenology of PSD is fundamentally different from that of long-term depression. PSD only occurs with pairings of trains of parallel fiber and climbing fiber stimulation; it occurs without the need for bicuculline; and it can overcome the blocking effects of aniracetam. 7. Nevertheless, the involvement of protein kinases and the potential role of calcium suggest that the mechanisms involved in the induction of PSD and long-term depression have a number of features in common. 8. Because of the pairing-specific nature of the long-term synaptic depression observed in these experiments, PSD provides a mechanism that may contribute to the role of the cerebellar cortex in classical conditioning.

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Inositol-1,4,5-Trisphosphate Receptor-Mediated Ca Mobilization Is Not Required for Cerebellar Long-Term Depression in Reduced Preparations

Journal of Neurophysiology ◽

10.1152/jn.1998.80.6.2963 ◽

1998 ◽

Vol 80 (6) ◽

pp. 2963-2974 ◽

Cited By ~ 26

Author(s):

Kalyani Narasimhan ◽

Isaac N. Pessah ◽

David J. Linden

Keyword(s):

Climbing Fiber ◽

Parallel Fiber ◽

Information Storage ◽

Ip3 Receptors ◽

Ip3 Receptor ◽

Long Term Depression ◽

Inositol 1,4,5 Trisphosphate ◽

Trisphosphate Receptor ◽

Fiber Stimulation

Narasimhan, Kalyani, Isaac N. Pessah, and David J. Linden. Inositol-1,4,5-trisphosphate receptor-mediated Ca mobilization is not required for cerebellar long-term depression in reduced preparations. J. Neurophysiol. 80: 2963–2974, 1998. Cerebellar long-term depression (LTD) is a cellular model system of information storage in which coincident parallel fiber and climbing fiber activation of a Purkinje neuron (PN) gives rise to a sustained attenuation of parallel fiber–PN synaptic strength. Climbing fiber and parallel fiber inputs may be replaced by direct depolarization of the PN and exogenous glutamate pulses, respectively. The parallel fiber–PN synapse has a high-density of mGluR1 receptors that are coupled to phosphoinositide turnover. Several lines of evidence indicated that activation of mGluR1 by parallel fiber stimulation is necessary for the induction of cerebellar LTD. Because phosphoinositide hydrolysis has two initial products, 1,2-diacylglycerol and inositol-1,4,5-trisphosphate (IP3), we wished to determine whether IP3 signaling via IP3 receptors and consequent Ca mobilization were necessary for the induction of cerebellar LTD. First, ratiometric imaging of free cytosolic Ca was performed on both acutely dissociated and cultured PNs. It was determined that the threshold for glutamate pulses to contribute to LTD induction was below the threshold for producing a Ca transient. Furthermore, the Ca transients produced by depolarization alone and glutamate plus depolarization were not significantly different. Second, the potent and selective IP3 receptor channel blocker xestospongin C was not found to affect the induction of LTD in either acutely dissociated or cultured PNs at a concentration that was sufficient to block mGluR1-evoked Ca mobilization. Third, replacement of mGluR activation by exogenous synthetic diacylglycerol in an LTD induction protocol was successful. Taken together, these results suggest that activation of an IP3 signaling cascade is not required for induction of cerebellar LTD in reduced preparations.

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Synaptic Plasticity in the Cerebellar Cortex and its Role in Motor Learning

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100048551 ◽

1993 ◽

Vol 20 (S3) ◽

pp. S70-S74 ◽

Cited By ~ 23

Author(s):

Ito Masao

Keyword(s):

Synaptic Plasticity ◽

Motor Performance ◽

Cognitive Learning ◽

Climbing Fiber ◽

Parallel Fiber ◽

Long Term Depression ◽

Learning Capability ◽

Transduction Mechanisms ◽

Cerebellar Purkinje Cells

ABSTRACT:Synaptic plasticity plays a role in the learning capability of brain tissues. Long-term depression (LTD) of parallel fiber synapses in cerebellar Purkinje cells occurs when these synapses are activated in conjunction with climbing fiber synapses. Signal transduction mechanisms underlying LTD have recently been investigated extensively. It has also become apparent that climbing fiber signals encode errors in the motor performance of an animal. It is therefore hypothesized that learning proceeds in cerebellar tissues in such a way that error signals of climbing fibers act to depress by LTD those parallel fiber synapses responsible for the errors. The cerebellum contains a large number of corticonuclear microcomplexes. Each microcomplex is connected to an extracerebellar system and is presumed to endow the system with learning capability. The hypothesis accounts for the adaptation of the vestibuloocular reflex and probably also for other forms of motor and cognitive learning.

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