Purkinje cell long-term depression is prevented by T-588, a neuroprotective compound that reduces cytosolic calcium release from intracellular stores

Kimura, Tatsuo; Sugimori, Mutsuyuki; Llinás, Rodolfó R.

doi:10.1073/pnas.0508190102

Cited by 27 publications

(21 citation statements)

References 44 publications

(47 reference statements)

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“…In particular, although experimental and traditional theoretical studies of LTD in pf synapses interpret these effects to be associated with Marr-Albus style (Albus 1971;Marr 1969) learning (for review see Oyhama et al 2003), this interpretation is tied to the idea that changes in pf synaptic strength result directly in changes in PC somatic output. Interpreted in the context of a circuit that depends on a balance between pf excitation and molecular layer inhibition, LTD might instead provide a mechanism to maintain that important balance (Bower 2002;De Schutter 1995) and thus is not a mechanism for classic synaptic learning (Kimura et al 2005).…”

Section: Inhibitory Influences Scale With Different Levels Of Pf Ac-mentioning

confidence: 99%

Feedforward Inhibition Controls the Spread of Granule Cell–Induced Purkinje Cell Activity in the Cerebellar Cortex

Santamarı́a¹,

Tripp²,

Bower³

2007

Journal of Neurophysiology

107

145

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Although most theories of cerebellar function assume these synapses produce an excitatory sequential "beamlike" activation of PCs, numerous physiological studies have failed to find such beams. Using a computer model of the cerebellar cortex we predicted that the lack of PCs beams is explained by the concomitant pf activation of feedforward molecular layer inhibition. This prediction was tested, in vivo, by recording PCs sharing a common set of pfs before and after pharmacologically blocking inhibitory inputs. As predicted by the model, pf-induced beams of excitatory PC responses were seen only when inhibition was blocked. Blocking inhibition did not have a significant effect in the excitability of the cerebellar cortex. We conclude that pfs work in concert with feedforward cortical inhibition to regulate the excitability of the PC dendrite without directly influencing PC spiking output. This conclusion requires a significant reassessment of classical interpretations of the functional organization of the cerebellar cortex. I N T R O D U C T I O NThe distinctive orthogonal projection of the parallel fibers (pfs) through Purkinje cells (PCs) in the cerebellar cortex has dominated speculations concerning cerebellar function for more than 100 years

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Section: Inhibitory Influences Scale With Different Levels Of Pf Ac-mentioning

confidence: 99%

Feedforward Inhibition Controls the Spread of Granule Cell–Induced Purkinje Cell Activity in the Cerebellar Cortex

Santamarı́a¹,

Tripp²,

Bower³

2007

Journal of Neurophysiology

107

145

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“…As demonstrated in the companion paper (9), the compound (1R)-1-benzo thiophen-5-yl-2[2-diethylamino)ethoxy] ethanol hydrochloride (T-588) prevents cerebellar LTD in vitro. When administered systemically, T-588 is neuroprotective, attenuates motoneuron death after nerve injury (10), and enhances performance on spatial learning tasks after brain ischemia (11).…”

mentioning

confidence: 94%

“…Here, we address these problems using a compound that prevents LTD in vitro (9) and in vivo. As demonstrated in the companion paper (9), the compound (1R)-1-benzo thiophen-5-yl-2[2-diethylamino)ethoxy] ethanol hydrochloride (T-588) prevents cerebellar LTD in vitro.…”

mentioning

confidence: 99%

Normal motor learning during pharmacological prevention of Purkinje cell long-term depression

Welsh

Yamaguchi

Zeng

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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130

105

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Systemic delivery of (1R-1-benzo thiophen-5-yl-2[2-diethylamino)-ethoxy] ethanol hydrochloride (T-588) prevented long-term depression (LTD) of the parallel fiber (PF)-Purkinje cell (PC) synapse induced by conjunctive climbing fiber and PF stimulation in vivo.However, similar concentrations of T-588 in the brains of behaving mice and rats affected neither motor learning in the rotorod test nor the learning of motor timing during classical conditioning of the eyeblink reflex. Rats given doses of T-588 that prevented PF-PC LTD were as proficient as controls in learning to adapt the timing of their conditioned eyeblink response to a 150-or 350-ms change in the timing of the paradigm. The experiment indicates that PF-PC LTD under control of the climbing fibers is not required for general motor adaptation or the learning of response timing in two common models of motor learning for which the cerebellum has been implicated. Alternative mechanisms for motor timing and possible functions for LTD in protection from excitotoxicity are discussed.cerebellum ͉ eyeblink ͉ field potentials ͉ rotorod A longstanding hypothesis concerning cerebellar function has been the proposal that it serves as the repository for new motor skills through plasticity of the parallel fiber (PF)-Purkinje cell (PC) synapse (1, 2). In the prevailing hypothesis of ''cerebellar learning,'' the acquisition of new skills is controlled by climbing fibers (CFs), which function to depress the strength of the PF-PC synapse when the two afferents are conjointly active. The cerebellar learning hypothesis has inspired much research since the demonstration, in vivo, that near-synchronous activation of CFs and PFs by direct electrical stimulation depressed the strength of the excitatory potentials triggered by PFs in PCs (3). Because the depression required repeated pairings of CF and PF synaptic input and was retained for many hours, the phenomenon has been termed cerebellar long-term depression (LTD) and has been invoked to explain the acquisition and lifetime retention of many motor skills, including learned motor timing, reflex adaptation, and procedural and implicit learning (4).A substantial body of evidence has established the necessary intracellular events that produce PC LTD in vitro, and these events have been assumed to relate to motor learning in vivo. Moreover, a recent experiment showed that mouse PCs genetically modified to lack protein kinase C (PKC) function could not undergo LTD (5, 6); when such transgenic mice were tested in classical eyeblink conditioning, they were unable to learn the appropriate motor timing of conditioned eyeblinks [conditioned response (CR)] (7). That finding, complemented by the finding that cerebellar decortication also impaired the learned motor timing of CRs (8), has sustained the hypothesis that PF-PC LTD is required for motor learning. However, it is also evident that, up to this time, it has not been determined whether LTD occurs in awake animals as they acquire and retain new motor skills. Thus, it has been diffic...

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“…It has been recently shown that PF-LTD is not required for learning a stimulus-response association (stimulus-dependent water Y-maze (SWYM) conditioning task that requires a goal-directed behavior), but a PKCdependent process in PC is required for optimization of motor responses (Burguière et al 2010). In addition, it has been proposed that this form of synaptic plasticity is not required for the mechanisms underlying cerebellar learning of motor timing in classical conditioning of the eyeblink reflex (Welsh et al 2005), but rather is a neuroprotective mechanism that prevents Ca 2+ -dependent PC damage by decreasing glutamate receptor sensitivity (Kimura et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Purkinje Neurons: Synaptic Plasticy

Daniel¹,

Crépel²

2013

Handbook of the Cerebellum and Cerebellar Disorders

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After three decades of research, it is now well established that molecular mechanisms underlying cerebellar motor learning lead to activity-dependent changes in synaptic strength, such as long-term depression (LTD) and longterm potentiation (LTP) at cerebellar parallel fiber (PF)-Purkinje cell (PC) glutamatergic synapses. This review focuses on mechanisms of these longterm changes in synaptic efficacy, even though short-term forms of synaptic plasticity also exist at these synapses and may also contribute to neural processing of information within the cerebellum. In light of the newly obtained experimental data from transgenic mice, it will also be discussed as to why these forms of synaptic plasticity are proposed as the cellular basis for error-driven learning and memory in the motor system.

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Purkinje cell long-term depression is prevented by T-588, a neuroprotective compound that reduces cytosolic calcium release from intracellular stores

Cited by 27 publications

References 44 publications

Feedforward Inhibition Controls the Spread of Granule Cell–Induced Purkinje Cell Activity in the Cerebellar Cortex

Feedforward Inhibition Controls the Spread of Granule Cell–Induced Purkinje Cell Activity in the Cerebellar Cortex

Normal motor learning during pharmacological prevention of Purkinje cell long-term depression

Purkinje Neurons: Synaptic Plasticy

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