Differential Maturation of the Two Regulated Secretory Pathways in Human iPSC-Derived Neurons

Javier Emperador Melero; Aishwarya G Nadadhur; Desiree Schut; Jan V Weering; Vivi M Heine; Ruud F Toonen; Matthijs Verhage

doi:10.1016/j.stemcr.2017.01.019

Differential Maturation of the Two Regulated Secretory Pathways in Human iPSC-Derived Neurons

Javier Emperador Melero, Aishwarya G Nadadhur, Desiree Schut, Jan V Weering, Vivi M Heine, Ruud F Toonen, Matthijs Verhage

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Neurons communicate by regulated secretion of chemical signals from synaptic vesicles (SVs) and dense-core vesicles (DCVs). Here, we investigated the maturation of these two secretory pathways in micro-networks of human iPSC-derived neurons. These micro-networks abundantly expressed endogenous SV and DCV markers, including neuropeptides. DCV transport was microtubule dependent, preferentially anterograde in axons, and 2-fold faster in axons than in dendrites. SV and DCV secretion were strictly Ca2+ and SNARE dependent. DCV secretion capacity matured until day in vitro (DIV) 36, with intense stimulation releasing 6% of the total DCV pool, and then plateaued. This efficiency is comparable with mature mouse neurons. In contrast, SV secretion capacity continued to increase until DIV50, with substantial further increase in secretion efficiency and decrease in silent synapses. These data show that the two secretory pathways can be studied in human neurons and that they mature differentially, with DCV secretion reaching maximum efficiency when that of SVs is still low.

Original language	English
Pages (from-to)	659-672
Number of pages	14
Journal	Stem cell reports
Volume	8
Issue number	3
DOIs	https://doi.org/10.1016/j.stemcr.2017.01.019
Publication status	Published - 14 Mar 2017

Funding

Funders	Funder number
Seventh Framework Programme	322966

Keywords

Animals
Axons
Biological Transport
Biomarkers
Calcium
Cell Differentiation
Dendrites
Humans
Induced Pluripotent Stem Cells
Journal Article
Mice
Microtubules
Neurons
Research Support, Non-U.S. Gov't
SNARE Proteins
Secretory Pathway
Secretory Vesicles
Synapses
Synaptic Transmission

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title = "Differential Maturation of the Two Regulated Secretory Pathways in Human iPSC-Derived Neurons",

abstract = "Neurons communicate by regulated secretion of chemical signals from synaptic vesicles (SVs) and dense-core vesicles (DCVs). Here, we investigated the maturation of these two secretory pathways in micro-networks of human iPSC-derived neurons. These micro-networks abundantly expressed endogenous SV and DCV markers, including neuropeptides. DCV transport was microtubule dependent, preferentially anterograde in axons, and 2-fold faster in axons than in dendrites. SV and DCV secretion were strictly Ca2+ and SNARE dependent. DCV secretion capacity matured until day in vitro (DIV) 36, with intense stimulation releasing 6% of the total DCV pool, and then plateaued. This efficiency is comparable with mature mouse neurons. In contrast, SV secretion capacity continued to increase until DIV50, with substantial further increase in secretion efficiency and decrease in silent synapses. These data show that the two secretory pathways can be studied in human neurons and that they mature differentially, with DCV secretion reaching maximum efficiency when that of SVs is still low.",

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AU - Emperador Melero, Javier

AU - Nadadhur, Aishwarya G

AU - Schut, Desiree

AU - Weering, Jan V

AU - Heine, Vivi M

AU - Toonen, Ruud F

AU - Verhage, Matthijs

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N2 - Neurons communicate by regulated secretion of chemical signals from synaptic vesicles (SVs) and dense-core vesicles (DCVs). Here, we investigated the maturation of these two secretory pathways in micro-networks of human iPSC-derived neurons. These micro-networks abundantly expressed endogenous SV and DCV markers, including neuropeptides. DCV transport was microtubule dependent, preferentially anterograde in axons, and 2-fold faster in axons than in dendrites. SV and DCV secretion were strictly Ca2+ and SNARE dependent. DCV secretion capacity matured until day in vitro (DIV) 36, with intense stimulation releasing 6% of the total DCV pool, and then plateaued. This efficiency is comparable with mature mouse neurons. In contrast, SV secretion capacity continued to increase until DIV50, with substantial further increase in secretion efficiency and decrease in silent synapses. These data show that the two secretory pathways can be studied in human neurons and that they mature differentially, with DCV secretion reaching maximum efficiency when that of SVs is still low.

AB - Neurons communicate by regulated secretion of chemical signals from synaptic vesicles (SVs) and dense-core vesicles (DCVs). Here, we investigated the maturation of these two secretory pathways in micro-networks of human iPSC-derived neurons. These micro-networks abundantly expressed endogenous SV and DCV markers, including neuropeptides. DCV transport was microtubule dependent, preferentially anterograde in axons, and 2-fold faster in axons than in dendrites. SV and DCV secretion were strictly Ca2+ and SNARE dependent. DCV secretion capacity matured until day in vitro (DIV) 36, with intense stimulation releasing 6% of the total DCV pool, and then plateaued. This efficiency is comparable with mature mouse neurons. In contrast, SV secretion capacity continued to increase until DIV50, with substantial further increase in secretion efficiency and decrease in silent synapses. These data show that the two secretory pathways can be studied in human neurons and that they mature differentially, with DCV secretion reaching maximum efficiency when that of SVs is still low.

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KW - Synaptic Transmission

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Differential Maturation of the Two Regulated Secretory Pathways in Human iPSC-Derived Neurons

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