Cerebellum

LLINÁS, RODOLFO R.; WALTON, KERRY D.; Lang, Eric J.

doi:10.1093/acprof:oso/9780195159561.003.0007

Cited by 77 publications

(78 citation statements)

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“…The cerebellum is deeply involved in learning motor skills [29,40,41] Our study demonstrated that during the same developmental period, functional GABAergic synapses are formed synapse and GABAergic inhibition starts in the cerebellar glomeruli [32,66,70,71]. Overall, these results suggested that the start of GABAergic inhibition is crucial for acquisition of motor learning.…”

Section: Formation and Maturation Of Gabaergic Synapses In The Cerebesupporting

confidence: 53%

Morphological development and maturation of the GABAergic synapses in the mouse cerebellar granular layer

Takayama¹,

Inoue²

2004

Developmental Brain Research

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In the adult central nervous system (CNS), γ-amino butyric acid (GABA) is a predominant inhibitory neurotransmitter, which regulates glutamatergic activity. Recent studies have revealed that GABA serves as an excitatory transmitter in the immature CNS, and is involved in brain morphogenesis. To elucidate how GABA exerts its effect on immature neurons and how GABAergic synapses are formed, we examined both development of pre-and post-synaptic elements of the GABAergic synapses formed between granule and Golgi cells in the mouse cerebellar granular layer. Immunohistochemistry for glutamic acid decarboxylase (GAD) demonstrated that GABA was localized throughout the Golgi cells before postnatal day 7 (P7), and became confined to the axon terminals during the second postnatal week. Electron microscopic analysis demonstrated that GABAergic synapses were clearly detected at P10. In situ hybridization and immunohistochemistry for the GABA A receptor α1 and α6 subunits, which are mainly involved in inhibitory synaptic transmission, demonstrated that both subunits appeared at P7. Distribution of both subunits expanded in the granular layer with special reference to the development of GABAergic synapses.Furthermore, the majority of the subunits accumulated adjacent to the GABAergic terminals.These results suggested that in the granular layer, GABA might be non-synaptically secreted from Golgi cell axons and dendrites during the first postnatal week. From the second postnatal week, GABA is synaptically released and begins to mediate inhibitory transmission.Furthermore, it was suggested that GABAergic innervation could initiate expression and trafficking of the GABA A receptors containing the α1 and α6 subunits.

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Section: Formation and Maturation Of Gabaergic Synapses In The Cerebesupporting

confidence: 53%

Morphological development and maturation of the GABAergic synapses in the mouse cerebellar granular layer

Takayama¹,

Inoue²

2004

Developmental Brain Research

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“…In contrast to these findings, blockade of granule cell transmission abolished firing of simple spikes in the DOX-treated awake animals. In the cerebellar cortical circuitry, basket, stellate, and Golgi interneurons receive granule cell transmission and could influence the responsiveness of Purkinje cells (5). However, these interneurons are all inhibitory and would facilitate firing of simple spikes by blockade of granule cell transmission.…”

Section: Discussionmentioning

confidence: 99%

“…This associative motor learning is a basic form of cerebellum-dependent leaning. In eyeblink conditioning, the CS pathway includes the pontine nucleus and mossy fibers, whereas the US pathway includes the inferior olive and the climbing fibers (1)(2)(3)(4)(5). The mossy fibers project directly to the interpositus nucleus and indirectly to the cerebellar cortex via granule cells (1)(2)(3)(4)(5).…”

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confidence: 99%

Conditioned eyeblink learning is formed and stored without cerebellar granule cell transmission

Wada

Kishimoto

Watanabe

et al. 2007

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

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), the authors note that in Fig. 2a, the same trace was inadvertently used for the electrophysiological records of RNB (DOXuntreated) and RNB (DOX-withdrawn). This error does not affect the conclusions of the article. The corrected figure and its legend appear below. (e and f ) Mean Ϯ SEM of firing rates of simple spikes (e) and complex spikes ( f) are shown with columns and bars, respectively. *** , P Ͻ 0.001 (comparison between DOX-treated RNB mice and all five other animals by the Scheffé test). (g) The extracellular recording site (red) was confirmed at the Purkinje cell layer by fluorescent Nissl staining. ML, molecular layer; PL, Purkinje cell layer; GL, granule cell layer. eyeblink conditioning ͉ interpositus nucleus ͉ Purkinje cell ͉ reversible neurotransmission blockade ͉ synaptic plasticity C lassical conditioning of the eyeblink reflex is elicited by paired presentation of conditioned stimulus (CS) with reinforcing unconditioned stimulus (US) (1-4). This associative motor learning is a basic form of cerebellum-dependent leaning. In eyeblink conditioning, the CS pathway includes the pontine nucleus and mossy fibers, whereas the US pathway includes the inferior olive and the climbing fibers (1-5). The mossy fibers project directly to the interpositus nucleus and indirectly to the cerebellar cortex via granule cells (1-5). The CS and US signals are thus conveyed to both the cerebellar cortex and the interpositus nucleus (Fig. 1a). The localization and underlying mechanisms of eyeblink conditioning have been extensively studied by different approaches including gene targeting (6-11), lesioning (12-15), mutant analysis (16), and pharmacological inactivation analyses (17-23). On the basis of these studies, one model proposes an essential role of the cerebellar Purkinje cell circuit in memory traces (24)(25)(26). According to this model, convergence of the CS and US signals induces long-term depression at the parallel fiber-Purkinje cell synapses. Because Purkinje cells are inhibitory, long-term depression causes a disinhibition of the interpositus nucleus and an increased input in the downstream motor pathways. The other model proposes that the memory trace is located in the interpositus nucleus and that conditioned responses (CRs) are properly evoked in response to CS by a timing signal from Purkinje cells (1,3,27,28). Eyeblink conditioning involves multiple learning processes, at least acquisition, expression, and storage of motor learning. Once the expression process of memory traces is impaired, it becomes difficult to define the key neural circuits responsible for expression, formation, and storage of memory traces.In this investigation, we adopted a novel reversible neurotransmission blocking (RNB) technique to explore the role of Purkinje cells and the interpositus nucleus in associative eyeblink conditioning. In the RNB transgenic mice, the tetanus toxin light chain is restrictedly expressed in granule cells under the control of a tetracycline-controlled reverse transactivator (rtTA) (29). Tetanus t...

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“…Normal PCs fire spontaneous APs under basal conditions, thereby tonically inhibiting the DCN (27). Surprisingly, Ͼ50% of the PCs from BK Ϫ/Ϫ mice lacked spontaneous discharge (8 of 15 cells, 53.3%), in sharp contrast to the WT cells, which all generated spontaneous APs during whole-cell recording (15 of 15 cells; Fig.…”

Section: Resultsmentioning

confidence: 94%

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency

Sausbier

Hu²,

Arntz³

et al. 2004

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

380

423

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Malfunctions of potassium channels are increasingly implicated as causes of neurological disorders. However, the functional roles of the large-conductance voltage-and Ca 2؉ -activated K ؉ channel (BK channel), a unique calcium, and voltage-activated potassium channel type have remained elusive. Here we report that mice lacking BK channels (BK ؊/؊ ) show cerebellar dysfunction in the form of abnormal conditioned eye-blink reflex, abnormal locomotion and pronounced deficiency in motor coordination, which are likely consequences of cerebellar learning deficiency. At the cellular level, the BK ؊/؊ mice showed a dramatic reduction in spontaneous activity of the BK ؊/؊ cerebellar Purkinje neurons, which generate the sole output of the cerebellar cortex and, in addition, enhanced short-term depression at the only output synapses of the cerebellar cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by the lack of postsynaptic BK channels were found to be due to depolarization-induced inactivation of the action potential mechanism. These results identify previously unknown roles of potassium channels in mammalian cerebellar function and motor control. In addition, they provide a previously undescribed animal model of cerebellar ataxia. P otassium channels are the largest and most diverse class of ion channels underlying electrical signaling in the brain (1). By causing highly regulated, time-dependent, and localized polarization of the cell membrane, the opening of K ϩ channels mediates feedback control of excitability in a variety of cell types and conditions (1). Consequently, K ϩ channel dysfunctions can cause a range of neurological disorders (2-6), and drugs that target K ϩ channels hold promise for a variety of clinical applications (7).Among the wide range of voltage-and calcium-gated K ϩ channel types, one stands out as unique: the large-conductance voltage-and Ca 2ϩ -activated K ϩ channel (BK channel, also termed Slo or Maxi-K) differs from all other K ϩ channels in that it can be activated by both intracellular Ca 2ϩ ions and membrane depolarization (8). These channels are widely expressed in central and peripheral neurons, as well as in other tissues (9), and are regarded as a promising drug target (10). However, the functions of the BK channels in vivo have not previously been directly tested in any vertebrate species. We therefore decided to examine the functions of these channels by inactivating the gene encoding the pore-forming channel protein. MethodsA complete description of the methods is given in Supporting Methods, which is published as supporting information on the PNAS web site.Generation of BK Channel ␣ Subunit-Deficient Mice. In the targeting vector (Fig. 5, which is published as supporting information on the PNAS web site), the pore exon was flanked by a single loxP site and a floxed neo͞tk cassette. Correctly targeted embryonic stem cells were injected into C57BL͞6 blastocysts and resulting chimeric mice mated with C57BL͞6. Homozygous BK-deficient mice (F 2 generation) ...

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Cerebellum

Cited by 77 publications

References 0 publications

Morphological development and maturation of the GABAergic synapses in the mouse cerebellar granular layer

Morphological development and maturation of the GABAergic synapses in the mouse cerebellar granular layer

Conditioned eyeblink learning is formed and stored without cerebellar granule cell transmission

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency

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Cerebellum

Cited by 77 publications

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Morphological development and maturation of the GABAergic synapses in the mouse cerebellar granular layer

Morphological development and maturation of the GABAergic synapses in the mouse cerebellar granular layer

Conditioned eyeblink learning is formed and stored without cerebellar granule cell transmission

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca 2+ -activated K + channel deficiency

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Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency