New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The α7 subtype of nAChRs is involved in neurological pathologies such as Parkinson's disease, Alzheimer's disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster α7 (Dα7) ha...

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Autores principales:	Monica Mejia, Mari D Heghinian, Frank Marí, Tanja A Godenschwege
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/91fed591b12c4f9595d74d4641f5e471
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spelling	oai:doaj.org-article:91fed591b12c4f9595d74d4641f5e4712021-11-18T07:43:47ZNew tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.1932-620310.1371/journal.pone.0064685https://doaj.org/article/91fed591b12c4f9595d74d4641f5e4712013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23737994/?tool=EBIhttps://doaj.org/toc/1932-6203Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The α7 subtype of nAChRs is involved in neurological pathologies such as Parkinson's disease, Alzheimer's disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster α7 (Dα7) has the closest sequence homology to the vertebrate α7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The Dα7 subunits are essential for the function of the Giant Fiber circuit, which mediates the escape response of the fly. To further characterize the receptor function, we generated different missense mutations in the Dα7 nAChR's ligand binding domain. We characterized the effects of targeted expression of two UAS-constructs carrying a single mutation, D197A and Y195T, as well as a UAS-construct carrying a triple D77T, L117Q, I196P mutation in a Dα7 null mutant and in a wild type background. Expression of the triple mutation was able to restore the function of the circuit in Dα7 null mutants and had no disruptive effects when expressed in wild type. In contrast, both single mutations severely disrupted the synaptic transmission of Dα7-dependent but not glutamatergic or gap junction dependent synapses in wild type background, and did not or only partially rescued the synaptic defects of the null mutant. These observations are consistent with the formation of hybrid receptors, consisting of D197A or Y195T subunits and wild type Dα7 subunits, in which the binding of acetylcholine or acetylcholine-induced conformational changes of the Dα7 receptor are altered and causes inhibition of cholinergic responses. Thus targeted expression of D197A or Y195T can be used to selectively disrupt synaptic transmission of Dα7-dependent synapses in neuronal circuits. Hence, these constructs can be used as tools to study learning and memory or addiction associated behaviors by allowing the manipulation of neuronal processing in the circuits without affecting other cellular signaling.Monica MejiaMari D HeghinianFrank MaríTanja A GodenschwegePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e64685 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Monica Mejia Mari D Heghinian Frank Marí Tanja A Godenschwege New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.
description	Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The α7 subtype of nAChRs is involved in neurological pathologies such as Parkinson's disease, Alzheimer's disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster α7 (Dα7) has the closest sequence homology to the vertebrate α7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The Dα7 subunits are essential for the function of the Giant Fiber circuit, which mediates the escape response of the fly. To further characterize the receptor function, we generated different missense mutations in the Dα7 nAChR's ligand binding domain. We characterized the effects of targeted expression of two UAS-constructs carrying a single mutation, D197A and Y195T, as well as a UAS-construct carrying a triple D77T, L117Q, I196P mutation in a Dα7 null mutant and in a wild type background. Expression of the triple mutation was able to restore the function of the circuit in Dα7 null mutants and had no disruptive effects when expressed in wild type. In contrast, both single mutations severely disrupted the synaptic transmission of Dα7-dependent but not glutamatergic or gap junction dependent synapses in wild type background, and did not or only partially rescued the synaptic defects of the null mutant. These observations are consistent with the formation of hybrid receptors, consisting of D197A or Y195T subunits and wild type Dα7 subunits, in which the binding of acetylcholine or acetylcholine-induced conformational changes of the Dα7 receptor are altered and causes inhibition of cholinergic responses. Thus targeted expression of D197A or Y195T can be used to selectively disrupt synaptic transmission of Dα7-dependent synapses in neuronal circuits. Hence, these constructs can be used as tools to study learning and memory or addiction associated behaviors by allowing the manipulation of neuronal processing in the circuits without affecting other cellular signaling.
format	article
author	Monica Mejia Mari D Heghinian Frank Marí Tanja A Godenschwege
author_facet	Monica Mejia Mari D Heghinian Frank Marí Tanja A Godenschwege
author_sort	Monica Mejia
title	New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.
title_short	New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.
title_full	New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.
title_fullStr	New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.
title_full_unstemmed	New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.
title_sort	new tools for targeted disruption of cholinergic synaptic transmission in drosophila melanogaster.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/91fed591b12c4f9595d74d4641f5e471
work_keys_str_mv	AT monicamejia newtoolsfortargeteddisruptionofcholinergicsynaptictransmissionindrosophilamelanogaster AT maridheghinian newtoolsfortargeteddisruptionofcholinergicsynaptictransmissionindrosophilamelanogaster AT frankmari newtoolsfortargeteddisruptionofcholinergicsynaptictransmissionindrosophilamelanogaster AT tanjaagodenschwege newtoolsfortargeteddisruptionofcholinergicsynaptictransmissionindrosophilamelanogaster
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New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.

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