Journal article
Presynaptic development is controlled by the core active zone proteins CAST/ELKS
The Journal of physiology, Vol.598(12), pp.2431-2452
06/2020
DOI: 10.1113/JP279736
PMCID: PMC7405068
PMID: 32304329
Abstract
CAST/ELKS are positive regulators of presynaptic growth and are suppressors of active zone expansion at the developing mouse calyx of Held. CAST/ELKS regulate all three Ca
2 subtype channel levels in the presynaptic terminal and not just Ca
2.1. The half-life of ELKS is on the timescale of days and not weeks. Synaptic transmission was not impacted by the loss of CAST/ELKS. CAST/ELKS are involved in pathways regulating morphological properties of presynaptic terminals during an early stage of circuit maturation.
Many presynaptic active zone (AZ) proteins have multiple regulatory roles that vary during distinct stages of neuronal circuit development. The CAST/ELKS protein family are evolutionarily conserved presynaptic AZ molecules that regulate presynaptic calcium channels, synaptic transmission and plasticity in the mammalian CNS. However, how these proteins regulate synapse development and presynaptic function in a developing neuronal circuit in its native environment is unclear. To unravel the roles of CAST/ELKS in glutamatergic synapse development and in presynaptic function, we used CAST knockout (KO) and ELKS conditional KO (CKO) mice to examine how their loss during the early stages of circuit maturation impacted the calyx of Held presynaptic terminal development and function. Morphological analysis from confocal z-stacks revealed that combined deletion of CAST/ELKS resulted in a reduction in the surface area and volume of the calyx. Analysis of AZ ultrastructure showed that AZ size was increased in the absence of CAST/ELKS. Patch clamp recordings demonstrated a reduction of all presynaptic Ca
2 channel subtype currents that correlated with a loss in presynaptic Ca
2 channel numbers. However, these changes did not impair synaptic transmission and plasticity and synaptic vesicle release kinetics. We conclude that CAST/ELKS proteins are positive regulators of presynaptic growth and are suppressors of AZ expansion and Ca
2 subtype currents and levels during calyx of Held development. We propose that CAST/ELKS are involved in pathways regulating presynaptic morphological properties and Ca
2 channel subtypes and suggest there is developmental compensation to preserve synaptic transmission during early stages of neuronal circuit maturation.
Details
- Title: Subtitle
- Presynaptic development is controlled by the core active zone proteins CAST/ELKS
- Creators
- Tamara Radulovic - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAWei Dong - Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Lab of Sichuan Province, Institute of Cardiovascular Research of Southwest Medical University, Luzhou, 646000, ChinaR Oliver Goral - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAConnon I Thomas - Electron Microscopy Facility, Max Planck Florida Institute for Neuroscience, Jupiter, FL, 33458, USAPriyadharishini Veeraraghavan - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAMonica Suarez Montesinos - Research Group Molecular Mechanisms of Synaptic Function, Max Planck Florida Institute for Neuroscience, Jupiter, FL, 33458, USADebbie Guerrero-Given - Electron Microscopy Facility, Max Planck Florida Institute for Neuroscience, Jupiter, FL, 33458, USAKevin Goff - Research Group Molecular Mechanisms of Synaptic Function, Max Planck Florida Institute for Neuroscience, Jupiter, FL, 33458, USAMatthias Lübbert - Research Group Molecular Mechanisms of Synaptic Function, Max Planck Florida Institute for Neuroscience, Jupiter, FL, 33458, USANaomi Kamasawa - Electron Microscopy Facility, Max Planck Florida Institute for Neuroscience, Jupiter, FL, 33458, USAToshihisa Ohtsuka - Department of Biochemistry , Graduate School of Medicine/Faculty of Medicine, University of Yamanashi, 1110 Shimokato Chuo, Yamanashi, 409-3898, JapanSamuel M Young Jr - Department of Otolaryngology, Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of physiology, Vol.598(12), pp.2431-2452
- Publisher
- England
- DOI
- 10.1113/JP279736
- PMID
- 32304329
- PMCID
- PMC7405068
- ISSN
- 0022-3751
- eISSN
- 1469-7793
- Grant note
- R01 DC014093 / NIDCD NIH HHS R01 NS110742 / NINDS NIH HHS
- Language
- English
- Date published
- 06/2020
- Academic Unit
- Anatomy and Cell Biology; Iowa Neuroscience Institute; Otolaryngology
- Record Identifier
- 9984070869802771
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