The metamorphosis of the developing cerebellar microcircuit

Welie, Ingrid van; Smith, Ikuko T.; Watt, Alanna J.

doi:10.1016/j.conb.2011.01.009

Cited by 32 publications

(29 citation statements)

References 72 publications

(90 reference statements)

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“…Therefore it is possible that some developmental factors that are essential for a correct formation of the network are missing. During development, granule cells migrate in the first two postnatal weeks from the external granular cell layer to the internal granule cell layer [49]. This migration is possibly impaired in organotypic slices because we observed in four week old cultures granular cells also near the molecular layer and not only in the internal granule cell layer (data not shown) which could speak for an insufficient maturation of the cerebellar network.…”

Section: Discussionmentioning

confidence: 74%

The Output Signal of Purkinje Cells of the Cerebellum and Circadian Rhythmicity

et al. 2013

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Measurement of clock gene expression has recently provided evidence that the cerebellum, like the master clock in the SCN, contains a circadian oscillator. The cerebellar oscillator is involved in anticipation of mealtime and possibly resides in Purkinje cells. However, the rhythmic gene expression is likely transduced into a circadian cerebellar output signal to exert an effective control of neuronal brain circuits that are responsible for feeding behavior. Using electrophysiological recordings from acute and organotypic cerebellar slices, we tested the hypothesis whether Purkinje cells transmit a circadian modulated signal to their targets in the brain. Extracellular recordings from brain slices revealed the typical discharge pattern previously described in vivo in single cell recordings showing basically a tonic or a trimodal-like firing pattern. However, in acute sagittal cerebellar slices the average spike rate of randomly selected Purkinje cells did not exhibit significant circadian variations, irrespective of their specific firing pattern. Also, frequency and amplitude of spontaneous inhibitory postsynaptic currents and the amplitude of GABA- and glutamate-evoked currents did not vary with circadian time. Long-term recordings using multielectrode arrays (MEA) allowed to monitor neuronal activity at multiple sites in organotypic cerebellar slices for several days to weeks. With this recording technique we observed oscillations of the firing rate of cerebellar neurons, presumably of Purkinje cells, with a period of about 24 hours which were stable for periods up to three days. The daily renewal of culture medium could induce circadian oscillations of the firing rate of Purkinje cells, a feature that is compatible with the behavior of slave oscillators. However, from the present results it appears that the circadian expression of cerebellar clock genes exerts only a weak influence on the electrical output of cerebellar neurons.

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Section: Discussionmentioning

confidence: 74%

The Output Signal of Purkinje Cells of the Cerebellum and Circadian Rhythmicity

et al. 2013

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“…Although ultrastructure analysis of disease-related Purkinje cell axonal torpedoes reveals that they do not contain vesicles (Petito et al, 1973; Yagishita, 1978; Mann et al, 1980; Louis et al, 2009), suggesting that they are not presynaptic release sites, we wondered whether developmental Purkinje cell axonal torpedoes might be the presynaptic structure of a transient synapse that functions during postnatal development. Interestingly, Purkinje cells form transient synapses onto other Purkinje cells during postnatal development (Watt et al, 2009), and transient synapses are thought to be a common feature of developing brain circuits (van Welie et al, 2011), and can also be found in other cerebellar neurons (Trigo et al, 2010). To examine whether developmental torpedoes were axon terminals containing vesicles, we used immunolabeling for vesicular GABA transporter (VGAT; Figure 4A ) (Watt et al, 2009), and quantified the number of torpedoes that colocalized with this presynaptic marker ( Figures 4A,B ).…”

Section: Resultsmentioning

confidence: 99%

“…The age at which torpedoes occur is a time of great restructuring in the developing cerebellum (McKay and Turner, 2005; van Welie et al, 2011; Hashimoto and Kano, 2013; White and Sillitoe, 2013). Several such transient changes have been identified in developing brain circuits that are thought to be involved in its proper development, including transient depolarization by GABAergic innervation (Ben-Ari, 2001, 2002), and transient electrical synapses (Fulton, 1995).…”

Section: Discussionmentioning

confidence: 99%

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

Ljungberg

Lang-Ouellette

Yang

et al. 2016

Front. Cell. Neurosci.

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Information is carried out of the cerebellar cortical microcircuit via action potentials propagated along Purkinje cell axons. In several human neurodegenerative diseases, focal axonal swellings on Purkinje cells – known as torpedoes – have been associated with Purkinje cell loss. Interestingly, torpedoes are also reported to appear transiently during development in rat cerebellum. The function of Purkinje cell axonal torpedoes in health as well as in disease is poorly understood. We investigated the properties of developmental torpedoes in the postnatal mouse cerebellum of wild-type and transgenic mice. We found that Purkinje cell axonal torpedoes transiently appeared on axons of Purkinje neurons, with the largest number of torpedoes observed at postnatal day 11 (P11). This was after peak developmental apoptosis had occurred, when Purkinje cell counts in a lobule were static, suggesting that most developmental torpedoes appear on axons of neurons that persist into adulthood. We found that developmental torpedoes were not associated with a presynaptic GABAergic marker, indicating that they are not synapses. They were seldom found at axonal collateral branch points, and lacked microglia enrichment, suggesting that they are unlikely to be involved in axonal refinement. Interestingly, we found several differences between developmental torpedoes and disease-related torpedoes: developmental torpedoes occurred largely on myelinated axons, and were not associated with changes in basket cell innervation on their parent soma. Disease-related torpedoes are typically reported to contain neurofilament; while the majority of developmental torpedoes did as well, a fraction of smaller developmental torpedoes did not. These differences indicate that developmental torpedoes may not be functionally identical to disease-related torpedoes. To study this further, we used a mouse model of spinocerebellar ataxia type 6 (SCA6), and found elevated disease-related torpedo number at 2 years. However, we found normal levels of developmental torpedoes in these mice. Our findings suggest that the transient emergence of Purkinje cell axonal torpedoes during the second postnatal week in mice represents a normal morphological feature in the developing cerebellar microcircuit.

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“…Interestingly, the synaptic and cellular changes observed in developing SCA6 84Q/84Q mice were transient, and these properties were indistinguishable from WT Purkinje cells from weanling (P21–24) mice, an age when climbing fibre and Purkinje cell firing properties have largely matured (McKay & Turner, ; van Welie et al . ; Hashimoto & Kano, ). Our results demonstrate that developmental perturbations do not necessarily cause detectable behavioural abnormalities, and that changes in circuit development may be transient.…”

Section: Introductionmentioning

confidence: 98%

Transient cerebellar alterations during development prior to obvious motor phenotype in a mouse model of spinocerebellar ataxia type 6

Jayabal

Ljungberg

Watt

2016

The Journal of Physiology

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Although some neurodegenerative diseases are caused by mutations in genes that are known to regulate neuronal development, surprisingly, patients may not present disease symptoms until adulthood. Spinocerebellar ataxia type 6 (SCA6) is one such midlife-onset disorder in which the mutated gene, CACNA1A, is implicated in cerebellar development. We wondered whether changes were observed in the developing cerebellum in SCA6 prior to the detection of motor deficits. To address this question, we used a transgenic mouse with a hyper-expanded triplet repeat (SCA6 ) that displays late-onset motor deficits at 7 months, and measured cerebellar Purkinje cell synaptic and intrinsic properties during postnatal development. We found that firing rate and precision were enhanced during postnatal development in P10-13 SCA6 Purkinje cells, and observed surplus multiple climbing fibre innervation without changes in inhibitory input or dendritic structure during development. Although excess multiple climbing fibre innervation has been associated with ataxic symptoms in several adult transgenic mice, we observed no detectable changes in cerebellar-related motor behaviour in developing SCA6 mice. Interestingly, we found that developmental alterations were transient, as both Purkinje cell firing properties and climbing fibre innervation from weanling-aged (P21-24) SCA6 mice were indistinguishable from litter-matched control mice. Our results demonstrate that significant alterations in neuronal circuit development may be observed without any detectable behavioural read-out, and that early changes in brain development may not necessarily persist into adulthood in midlife-onset diseases.

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The metamorphosis of the developing cerebellar microcircuit

Cited by 32 publications

References 72 publications

The Output Signal of Purkinje Cells of the Cerebellum and Circadian Rhythmicity

The Output Signal of Purkinje Cells of the Cerebellum and Circadian Rhythmicity

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

Transient cerebellar alterations during development prior to obvious motor phenotype in a mouse model of spinocerebellar ataxia type 6

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