Agrin mediates a rapid switch from electrical coupling to chemical neurotransmission during synaptogenesis

Agnès O. Martin, Gérard Alonso, , and Nathalie C. Guérineau

CNRS UMR5203, INSERM U661, Universités Montpellier I et II, Département d'Endocrinologie, Institut de Génomique Fonctionnelle, 34094 Montpellier Cedex 5, France

Correspondence to Nathalie C. Guérineau: nathalie.guerineau{at}igf.cnrs.fr

Abstract: In contrast to its well-established actions as an organizer of synaptic differentiation at the neuromuscular junction, the proteoglycan agrin is still in search of a function in the nervous system. Here, we report an entirely unanticipated role for agrin in the dual modulation of electrical and chemical intercellular communication that occurs during the critical period of synapse formation. When applied at the developing splanchnic nerve–chromaffin cell cholinergic synapse in rat adrenal acute slices, agrin rapidly modified cell-to-cell communication mechanisms. Specifically, it led to decreased gap junction–mediated electrical coupling that preceded an increase in nicotinic synaptic transmission. This developmental switch from predominantly electrical to chemical communication was fully operational within one hour and depended on the activation of Src family–related tyrosine kinases. Hence, agrin may play a pivotal role in synaptogenesis in promoting a rapid switch between electrical coupling and synaptic neurotransmission.

A.O. Martin's present address is Division of Molecular Neurobiology, National Institute for Medical Research, the Ridgeway, Mill Hill, London NW7 1AA, England, UK.

Abbreviations used in this paper: -Bgt, -bungarotoxin; CNS, central nervous system; Cx43, connexin-43; Gj, macroscopic junctional conductance; Ij, intercellular macroscopic junctional current; LY, Lucifer yellow; MuSK, muscle-specific kinase; NMJ, neuromuscular junction; nAChR, nicotinic acetylcholine receptor; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; PP3, 4-amino-7-phenylpyrazolo[3,4-d]pyrimidine; sEPSC, spontaneous excitatory postsynaptic current; TH, tyrosine hydroxylase; VAChT, vesicular acetylcholine transporter.

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