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Epigenetic Regulation of Neocortical Inhibitory Circuitry through DNA Methylation.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Epigenetic Regulation of Neocortical Inhibitory Circuitry through DNA Methylation./
Author:	Flyax, Alexander V.
Description:	1 online resource (126 pages)
Notes:	Source: Dissertation Abstracts International, Volume: 75-01(E), Section: B.
Subject:	Neurosciences. -
Online resource:	click for full text (PQDT)
ISBN:	9781303440366

Epigenetic Regulation of Neocortical Inhibitory Circuitry through DNA Methylation.
Flyax, Alexander V.

Epigenetic Regulation of Neocortical Inhibitory Circuitry through DNA Methylation. - 1 online resource (126 pages)

Source: Dissertation Abstracts International, Volume: 75-01(E), Section: B.

Thesis (Ph.D.)--Brandeis University, 2013.

Includes bibliographical references

Epigenetic regulation of gene transcription has received much attention in the study of the development of mammalian tissues. DNA methylation is a well-known epigenetic mechanism for regulation of gene expression; maintenance of existing methylation patterns is known to be important for stability of cell line identity, while de novo methylation is crucial for proliferation of cell lines. On the other hand, DNA methyltransferases (DNMTs), enzymes catalyzing DNA methylation, were not known until recently to have a functional role in maturing and adult post-mitotic neurons. New evidence suggests, however, that dynamic control of DNA methylation is important in the maturation of central nervous system, a number of neurological disorders, and normal neurological functions such as plasticity or memory. A number of studies have investigated the role of DNMTs in the excitatory neurons of the central nervous system. No studies, however, have examined their role in inhibitory neuronal circuitry despite the latter's crucial importance in the nervous system.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2018

Mode of access: World Wide Web

ISBN: 9781303440366Subjects--Topical Terms:

593561
Neurosciences.
Index Terms--Genre/Form:

554714
Electronic books.

Epigenetic Regulation of Neocortical Inhibitory Circuitry through DNA Methylation.
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245 1 0 $a Epigenetic Regulation of Neocortical Inhibitory Circuitry through DNA Methylation.
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500 $a Source: Dissertation Abstracts International, Volume: 75-01(E), Section: B.
500 $a Adviser: Sacha B. Nelson.
502 $a Thesis (Ph.D.)--Brandeis University, 2013.
504 $a Includes bibliographical references
520 $a Epigenetic regulation of gene transcription has received much attention in the study of the development of mammalian tissues. DNA methylation is a well-known epigenetic mechanism for regulation of gene expression; maintenance of existing methylation patterns is known to be important for stability of cell line identity, while de novo methylation is crucial for proliferation of cell lines. On the other hand, DNA methyltransferases (DNMTs), enzymes catalyzing DNA methylation, were not known until recently to have a functional role in maturing and adult post-mitotic neurons. New evidence suggests, however, that dynamic control of DNA methylation is important in the maturation of central nervous system, a number of neurological disorders, and normal neurological functions such as plasticity or memory. A number of studies have investigated the role of DNMTs in the excitatory neurons of the central nervous system. No studies, however, have examined their role in inhibitory neuronal circuitry despite the latter's crucial importance in the nervous system.
520 $a In Chapter I of this thesis, in Part A, I briefly review the functional role of DNA methylation in regulation of gene transcription (including some recent controversial evidence suggesting that its effects may be more multivariate than originally suspected), as well as its role in the development and in the nervous system. In Part B, I switch to the discussion of parvalbumin-positive fast-spiking (PV-FS) interneurons, a subclass of inhibitory neurons in the central nervous system that plays an important role in circuit- and network-level brain physiology and has been implicated in a number of neurological disorders.
520 $a In this study, I have investigated the effects of conditionally knocking out DNMTs 1 and 3a (two DNMTs present in the adult mammalian brain) in PV-FS cells on previously described phenotypic maturation of these neurons' physiological properties and strength of excitatory afferent inputs. I report the results in Chapter II. I have discovered that knocking out DNMTs leads to an increase in intrinsic excitability of PV-FS interneurons and a decrease in the strength of excitatory, but not inhibitory, synaptic input. My findings also suggest different targets of methylation for DNMTs 1 and 3a, at least in relation to the observed effects.
520 $a Methyl-CpG-binding protein 2 (Mecp2) belongs to a family of methyl-DNA-binding proteins. Its mutation leads to a debilitating neurological disorder, Rett Syndrome, and its function has been implicated in the maintenance of balance of excitation and inhibition in neocortical circuitry. It binds methylated DNA, acts globally in the genome, but has been reported to have both suppressing and activating effects on gene transcription. Because I have observed some drastic effects of knocking out DNMTs 1 and 3a on the excitatory inputs to PV-FS interneurons, I thought it important to investigate the role Mecp2 plays in normal development of this aspect of neocortical connectivity. I report the results in Chapter III. I have observed no effect on amplitude of miniature excitatory post-synaptic currents but an increase of their frequency, an intriguing result in light of my findings in DNMT knockouts. At the same time, I observed a similar effect on intrinsic excitability DNMT and Mecp2 knockouts.
520 $a In Chapter IV, I provide a brief summary of my results and a list of currently ongoing experiments, as well as future investigative directions.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2018
538 $a Mode of access: World Wide Web
650 4 $a Neurosciences. $3 593561
655 7 $a Electronic books. $2 local $3 554714
690 $a 0317
710 2 $a ProQuest Information and Learning Co. $3 1178819
710 2 $a Brandeis University. $b Neuroscience. $3 1186668
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3596770 $z click for full text (PQDT)