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Postsynaptic P/Q-type Ca2+ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum.

ABSTRACT: Neural circuits are initially redundant but rearranged through activity-dependent synapse elimination during postnatal development. This process is crucial for shaping mature neural circuits and for proper brain function. At birth, Purkinje cells (PCs) in the cerebellum are innervated by multiple climbing fibers (CFs) with similar synaptic strengths. During postnatal development, a single CF is selectively strengthened in each PC through synaptic competition, the strengthened single CF undergoes translocation to a PC dendrite, and massive elimination of redundant CF synapses follows. To investigate the cellular mechanisms of this activity-dependent synaptic refinement, we generated mice with PC-selective deletion of the Ca(v)2.1 P/Q-type Ca(2+) channel, the major voltage-dependent Ca(2+) channel in PCs. In the PC-selective Ca(v)2.1 knockout mice, Ca(2+) transients induced by spontaneous CF inputs are markedly reduced in PCs in vivo. Not a single but multiple CFs were equally strengthened in each PC from postnatal day 5 (P5) to P8, multiple CFs underwent translocation to PC dendrites, and subsequent synapse elimination until around P12 was severely impaired. Thus, P/Q-type Ca(2+) channels in postsynaptic PCs mediate synaptic competition among multiple CFs and trigger synapse elimination in developing cerebellum.

SUBMITTER: Hashimoto K

PROVIDER: S-EPMC3116426 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Postsynaptic P/Q-type Ca2+ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum.

Hashimoto Kouichi K Tsujita Mika M Miyazaki Taisuke T Kitamura Kazuo K Yamazaki Maya M Shin Hee-Sup HS Watanabe Masahiko M Sakimura Kenji K Kano Masanobu M

Proceedings of the National Academy of Sciences of the United States of America 20110531 24

Neural circuits are initially redundant but rearranged through activity-dependent synapse elimination during postnatal development. This process is crucial for shaping mature neural circuits and for proper brain function. At birth, Purkinje cells (PCs) in the cerebellum are innervated by multiple climbing fibers (CFs) with similar synaptic strengths. During postnatal development, a single CF is selectively strengthened in each PC through synaptic competition, the strengthened single CF undergoes ...[more]

PMID: 21628556

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Project description:Cerebellar damage early in life often causes long-lasting motor, social and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviours. This recent finding has promoted research on how cerebellar damage affects the development of the cerebral cortex, the brain region responsible for higher-order control of all behaviours. However, the cerebral cortex is not directly connected to the cerebellum. The thalamus is a major direct target of the cerebellar nuclei, conveying cerebellar signals to the cerebral cortex. Despite its crucial position in cerebello-cerebral interaction, thalamic susceptibility to cerebellar damage remains largely unclear. Here, we studied the consequences of early cerebellar perturbation on thalamic development. Whole-cell patch-clamp recordings showed that the synaptic organization of the cerebellothlamic circuit is similar to that of the primary sensory thalamus, in which aberrant sensory activity alters synaptic circuit formation. The ablation of Purkinje cells in the developing cerebellum strengthened cerebellothalamic synapses and enhanced thalamic suprathreshold activities. Purkinje-cell specific deletion of tuberous sclerosis complex subunit 1 (Tsc1), an autism-associated gene for which the protein product negatively regulates the mammalian target of rapamycin, also strengthened cerebellothalamic synapses. However, this strengthening occurred only in homozygous deletion, whereas both homozygous and hemizygous deletion are known to cause autism-like behaviours. These results suggest that, although the cerebellothalamic projection is vulnerable to disturbances in the developing cerebellar cortex, other changes may also drive the behavioural consequences of early cerebellar perturbation. KEY POINTS: Cerebellar damage early in life often causes motor, social and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviours. Recent studies focus on how the developing cerebellum affects the formation and function of the cerebral cortex, the higher-order centre for all behaviours. However, the cerebellum does not directly connect to the cerebral cortex. Here, we studied the consequences of early cerebellar perturbation on the thalamus because it is a direct postsynaptic target of the cerebellum, sending cerebellar signals to the cerebral cortex. Loss of cerebellar Purkinje cells, which are commonly associated with various neurological disorders, strengthened cerebellothalamic synapses, suggesting the vulnerability of the thalamus to substantial disturbance in the developing cerebellum. Purkinje cell-specific loss of tuberous sclerosis complex-1, a negative regulator of mammalian target of rapamycin, is an established mouse model of autism. This mouse model also showed strengthened cerebellothalamic synapses.

Dataset Information

Postsynaptic P/Q-type Ca2+ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum.

Publications

Postsynaptic P/Q-type Ca2+ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum.

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