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The transcription factor ZFP64 promotes activity-dependent synapse elimination during postnatal cerebellar
Jianling Zhang1,2, Takaki Watanabe1,2,3, Taisuke Miyazaki4
1Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Insights
The transcription factor ZFP64 in Purkinje cells (PCs) is crucial for eliminating extra climbing fiber (CF) synapses during early brain development. Its regulation of semaphorin 3A (Sema3A) expression is key for this essential neural circuit refinement.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Synapse elimination is vital for mature neural circuit formation.
- Purkinje cells (PCs) prune multiple climbing fiber (CF) inputs to a single innervation during development.
- Mechanisms governing this synapse elimination are not fully understood.
Purpose of the Study:
- To investigate the role of transcription factor ZFP64 in PC-mediated CF synapse elimination.
- To explore the relationship between ZFP64, P/Q-type voltage-dependent Ca2+ channels (P/Q-VDCCs), and semaphorin 3A (Sema3A) in this process.
Main Methods:
- PC-specific knockdown (KD) of ZFP64 in neonatal mice.
- Analysis of CF synapse elimination and innervation patterns.
- KD of semaphorin 3A (Sema3A) in PCs.
Main Results:
- PC-specific ZFP64 KD delayed redundant CF synapse elimination and CF innervation.
- ZFP64 KD effects were partially rescued by Sema3A KD.
- P/Q-VDCC KD effects were also partially rescued by Sema3A KD, suggesting ZFP64 acts downstream.
Conclusions:
- ZFP64 in PCs plays a significant role in developmental CF synapse elimination.
- ZFP64 likely promotes synapse elimination by regulating Sema3A expression.
- This pathway involving ZFP64, P/Q-VDCCs, and Sema3A is critical for cerebellar circuit maturation.
Abstract:
Eliminating redundant synapses formed around birth is essential for shaping functionally mature neural circuits during postnatal development. Each Purkinje cell (PC) in the neonatal mouse cerebellum receives synaptic inputs from multiple climbing fibers (CFs). Only one CF is strengthened and extends its innervation over PC dendrites, whereas the other CFs are eventually pruned during postnatal development. These events are believed to require proper gene expression, but the underlying mechanisms are not yet understood. Here, we report that the transcription factor ZFP64 in PCs mediates part of CF synapse elimination events presumably downstream of P/Q-type voltage-dependent Ca2+ channels (P/Q-VDCCs). PC-specific knockdown (KD) of ZFP64 during postnatal development delayed the elimination of redundant CF synapses and the dendritic extension of CF innervation. The KD of semaphorin 3A (Sema3A) in PCs partially restored the effects of ZFP64 or P/Q-VDCC KD. We propose that ZFP64 promotes developmental CF synapse elimination by regulating Sema3A expression.
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