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Synaptic mechanisms of OPRM1 A118G single nucleotide polymorphism in human neurons
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Halikere, Apoorva. Synaptic mechanisms of OPRM1 A118G single nucleotide polymorphism in human neurons. Retrieved from https://doi.org/doi:10.7282/T3VQ3632

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TitleSynaptic mechanisms of OPRM1 A118G single nucleotide polymorphism in human neurons
NameHalikere, Apoorva (author); Pang, Zhiping (chair); Pintar, John E (internal member); Hart, Ronald P (internal member); Blendy, Julie A (outside member); Rutgers University; School of Graduate Studies
Date Created2018
Other Date2018-05 (degree)
SubjectNeuroscience, Opioids--Receptors
Extent1 online resource (xiii, 157 p. : ill.)
DescriptionAssociation 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.
NotePh.D.
NoteIncludes bibliographical references
Noteby Apoorva Halikere
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3VQ3632
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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