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

Martin AO, Alonso G, Guérineau NC - J. Cell Biol. (2005)

Bottom Line: When applied at the developing splanchnic nerve-chromaffin cell cholinergic synapse in rat adrenal acute slices, agrin rapidly modified cell-to-cell communication mechanisms.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.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR5203, INSERM U661, Université Montpellier I, Département d'Endocrinologie, Institut de Génomique Fonctionnelle, 34094 Montpellier Cedex 5, France.

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.

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Related in: MedlinePlus

Agrin-induced recruitment of α-Bgt–sensitive nAChRs in neonates. (A) Effect of 200 μM hexamethonium and 10 μg/ml α-Bgt on sEPSCs in neonates and adults. In neonates, sEPSCs were fully blocked by hexamethonium. After exposure to agrin, the complete inhibition of sEPSCs required the additional application of α-Bgt, as in adults. (B) Pooled data summarizing the effects of hexamethonium on sEPSC frequency and amplitude. *, P < 0.01 when compared with untreated slices. (C) Effect of agrin treatment on the expression pattern of α7 nAChRs stained with Alexa 488–labeled α-Bgt.
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fig3: Agrin-induced recruitment of α-Bgt–sensitive nAChRs in neonates. (A) Effect of 200 μM hexamethonium and 10 μg/ml α-Bgt on sEPSCs in neonates and adults. In neonates, sEPSCs were fully blocked by hexamethonium. After exposure to agrin, the complete inhibition of sEPSCs required the additional application of α-Bgt, as in adults. (B) Pooled data summarizing the effects of hexamethonium on sEPSC frequency and amplitude. *, P < 0.01 when compared with untreated slices. (C) Effect of agrin treatment on the expression pattern of α7 nAChRs stained with Alexa 488–labeled α-Bgt.

Mentions: As recently described (Martin et al., 2003), sEPSCs recorded in adults are mediated by the coactivation of α3 and α7 nAChR subtypes that are antagonized by hexamethonium and α-bungarotoxin (α-Bgt), respectively. In neonate control slices, bath-applied hexamethonium (200 μM) fully inhibited sEPSCs (Fig. 3, A and B), pointing to a major contribution of the α3 subunit–containing nAChRs. In agrin-treated slices, hexamethonium only partly reduced sEPSCs, and as found in adults the remaining synaptic activity was blocked by subsequent application of α-Bgt (10 μg/ml). These results indicate that a change in the nAChR subtype distribution takes place during postnatal development at the splanchnic nerve–chromaffin cell cholinergic synapse. To test this hypothesis, α7 nAChRs were labeled in living slices using Alexa 488–conjugated α-Bgt. As illustrated in Fig. 3 C, prolonged agrin exposure (4–5 h) modified the expression pattern of fluorescent α7 nAChRs by promoting the formation of numerous nAChR aggregates, thus resembling the distribution found in adults.


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

Martin AO, Alonso G, Guérineau NC - J. Cell Biol. (2005)

Agrin-induced recruitment of α-Bgt–sensitive nAChRs in neonates. (A) Effect of 200 μM hexamethonium and 10 μg/ml α-Bgt on sEPSCs in neonates and adults. In neonates, sEPSCs were fully blocked by hexamethonium. After exposure to agrin, the complete inhibition of sEPSCs required the additional application of α-Bgt, as in adults. (B) Pooled data summarizing the effects of hexamethonium on sEPSC frequency and amplitude. *, P < 0.01 when compared with untreated slices. (C) Effect of agrin treatment on the expression pattern of α7 nAChRs stained with Alexa 488–labeled α-Bgt.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2171940&req=5

fig3: Agrin-induced recruitment of α-Bgt–sensitive nAChRs in neonates. (A) Effect of 200 μM hexamethonium and 10 μg/ml α-Bgt on sEPSCs in neonates and adults. In neonates, sEPSCs were fully blocked by hexamethonium. After exposure to agrin, the complete inhibition of sEPSCs required the additional application of α-Bgt, as in adults. (B) Pooled data summarizing the effects of hexamethonium on sEPSC frequency and amplitude. *, P < 0.01 when compared with untreated slices. (C) Effect of agrin treatment on the expression pattern of α7 nAChRs stained with Alexa 488–labeled α-Bgt.
Mentions: As recently described (Martin et al., 2003), sEPSCs recorded in adults are mediated by the coactivation of α3 and α7 nAChR subtypes that are antagonized by hexamethonium and α-bungarotoxin (α-Bgt), respectively. In neonate control slices, bath-applied hexamethonium (200 μM) fully inhibited sEPSCs (Fig. 3, A and B), pointing to a major contribution of the α3 subunit–containing nAChRs. In agrin-treated slices, hexamethonium only partly reduced sEPSCs, and as found in adults the remaining synaptic activity was blocked by subsequent application of α-Bgt (10 μg/ml). These results indicate that a change in the nAChR subtype distribution takes place during postnatal development at the splanchnic nerve–chromaffin cell cholinergic synapse. To test this hypothesis, α7 nAChRs were labeled in living slices using Alexa 488–conjugated α-Bgt. As illustrated in Fig. 3 C, prolonged agrin exposure (4–5 h) modified the expression pattern of fluorescent α7 nAChRs by promoting the formation of numerous nAChR aggregates, thus resembling the distribution found in adults.

Bottom Line: When applied at the developing splanchnic nerve-chromaffin cell cholinergic synapse in rat adrenal acute slices, agrin rapidly modified cell-to-cell communication mechanisms.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.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR5203, INSERM U661, Université Montpellier I, Département d'Endocrinologie, Institut de Génomique Fonctionnelle, 34094 Montpellier Cedex 5, France.

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.

Show MeSH
Related in: MedlinePlus