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Synaptic mechanisms of OPRM1 A118G single nucleotide polymorphism in human neurons

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Title
Synaptic mechanisms of OPRM1 A118G single nucleotide polymorphism in human neurons
Name (type = personal)
NamePart (type = family)
Halikere
NamePart (type = given)
Apoorva
NamePart (type = date)
1989-
DisplayForm
Apoorva Halikere
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
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Pang
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Zhiping
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Zhiping Pang
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Pintar
NamePart (type = given)
John E
DisplayForm
John E Pintar
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Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Hart
NamePart (type = given)
Ronald P
DisplayForm
Ronald P Hart
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Blendy
NamePart (type = given)
Julie A
DisplayForm
Julie A Blendy
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2018
DateOther (qualifier = exact); (type = degree)
2018-05
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2018
Place
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xx
Language
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eng
Abstract (type = abstract)
Association of the non-synonymous single nucleotide polymorphism (SNP) rs1799971 in OPRM1 to drug dependence and alcohol abuse suggests it may have a functional consequence in altering receptor signaling in the brain. The A118G SNP causes a switch of asparagine (N) at position 40 of the mu-opioid receptor (MOR) to aspartate (D). To dissect the underlying neural and synaptic basis of the N40D MOR variant, we generated human GABAergic induced neuronal (iN) cells from induced pluripotent stem (iPS) cells of donors homozygous for either the major (N40) or minor (D40) alleles of the MOR. We found that the subject-derived iN cells exhibit mature neuronal properties such as action potential firing and neuronal excitability and express functional MORs. Interestingly, upon MOR activation by the agonist DAMGO, D40 MOR iN cells exhibit consistently stronger suppression of spontaneous inhibitory postsynaptic currents (sIPSCs) than N40 MOR iN cells across multiple subjects. To mitigate the complexity of diverse genetic backgrounds of the subject iN cells derived from multiple human subjects, we employed CRISPR/Cas9 genome-editing to generate two pairs of isogenic human pluripotent stem cell lines. Remarkably, the synaptic regulation of MOR activation in the isogenic lines recapitulate those of neurons generated from different individuals, i.e. stronger suppression in D40 MOR carrying human neuronal cells by MOR activation. We further determined that the increased sensitivity of D40 iN cells to DAMGO was caused by a more robust inhibition of excitability and synaptic release by DAMGO in D40 MOR expressing neurons. Additionally, we found that the N40D SNP influences the development of long-term tolerance at the MOR. Specifically, D40 iN cells are unable to develop adaptive changes in synaptic function unlike N40 iN cells following long-term mu opioid receptor activation by DAMGO. This study utilizes patient-specific iPS cells as well as a gene edited isogenic neurons to advance our understanding of the fundamental synaptic alterations associated with OPRM1 A118G in a human neuronal context.
Subject (authority = RUETD)
Topic
Neuroscience
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_8703
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xiii, 157 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = ETD-LCSH)
Topic
Opioids--Receptors
Note (type = statement of responsibility)
by Apoorva Halikere
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3VQ3632
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Halikere
GivenName
Apoorva
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-03-14 11:15:00
AssociatedEntity
Name
Apoorva Halikere
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2020-05-30
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 30th, 2020.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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2018-03-14T10:15:19
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