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Dynamin 1- and 3-Mediated Endocytosis Is Essential for the Development of a Large Central Synapse In Vivo. J Neurosci 2016 Jun 01;36(22):6097-115

Date

06/03/2016

Pubmed ID

27251629

Pubmed Central ID

PMC4887570

DOI

10.1523/JNEUROSCI.3804-15.2016

Scopus ID

2-s2.0-84971673132 (requires institutional sign-in at Scopus site)   30 Citations

Abstract

UNLABELLED: Dynamin is a large GTPase crucial for endocytosis and sustained neurotransmission, but its role in synapse development in the mammalian brain has received little attention. We addressed this question using the calyx of Held (CH), a large nerve terminal in the auditory brainstem in mice. Tissue-specific ablation of different dynamin isoforms bypasses the early lethality of conventional knock-outs and allows us to examine CH development in a native brain circuit. Individual gene deletion of dynamin 1, a primary dynamin isoform in neurons, as well as dynamin 2 and 3, did not affect CH development. However, combined tissue-specific knock-out of both dynamin 1 and 3 (cDKO) severely impaired CH formation and growth during the first postnatal week, and the phenotypes were exacerbated by further additive conditional knock-out of dynamin 2. The developmental defect of CH in cDKO first became evident on postnatal day 3 (P3), a time point when CH forms and grows abruptly. This is followed by a progressive loss of postsynaptic neurons and increased glial infiltration late in development. However, early CH synaptogenesis before protocalyx formation was not altered in cDKO. Functional maturation of synaptic transmission in the medial nucleus of the trapezoid body in cDKO was impeded during development and accompanied by an increase in the membrane excitability of medial nucleus of the trapezoid body neurons. This study provides compelling genetic evidence that CH formation requires dynamin 1- and 3-mediated endocytosis in vivo, indicating a critical role of dynamin in synaptic development, maturation, and subsequent maintenance in the mammalian brain.

SIGNIFICANCE STATEMENT: Synaptic development has been increasingly implicated in numerous brain disorders. Dynamin plays a crucial role in clathrin-mediated endocytosis and synaptic transmission at nerve terminals, but its potential role in synaptic development in the native brain circuitry is unclear. Using the calyx of Held, a giant nerve terminal in the mouse brainstem, we evaluated the role of dynamin in this process by using tissue-specific knock-out (KO) of three different dynamin isoforms (dynamin 1, 2, and 3) individually and in combination. Our data demonstrated that dynamin is required for the formation, functional maturation, and subsequent survival of the calyx of Held. This study highlights the important role of dynamin-mediated endocytosis in the development of central synapses in the mammalian brain.

Author List

Fan F, Funk L, Lou X

Author

Xuelin Lou PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Age Factors
Animals
Animals, Newborn
Brain Stem
Dynamin I
Dynamin III
Early Growth Response Protein 2
Electric Stimulation
Endocytosis
Ether-A-Go-Go Potassium Channels
Excitatory Postsynaptic Potentials
Gene Expression Regulation, Developmental
In Vitro Techniques
Mice
Mice, Transgenic
Patch-Clamp Techniques
Synapses
Vesicular Glutamate Transport Protein 1