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GABA maintains the proliferation of progenitors in the developing chick ciliary marginal zone and non-pigmented ciliary epithelium:      
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience. (Finn Hallböök)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. (Bryndis Birnir)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience. (Finn Hallböök)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, e36874- p.Article in journal (Refereed) Published
Abstract [en]

GABA is more than the main inhibitory neurotransmitter found in the adult CNS. Several studies have shown that GABA regulates the proliferation of progenitor and stem cells. This work examined the effects of the GABA(A) receptor system on the proliferation of retinal progenitors and non-pigmented ciliary epithelial (NPE) cells. qRT-PCR and whole-cell patch-clamp electrophysiology were used to characterize the GABA(A) receptor system. To quantify the effects on proliferation by GABA(A) receptor agonists and antagonists, incorporation of thymidine analogues was used. The results showed that the NPE cells express functional extrasynaptic GABA(A) receptors with tonic properties and that low concentration of GABA is required for a baseline level of proliferation. Antagonists of the GABA(A) receptors decreased the proliferation of dissociated E12 NPE cells. Bicuculline also had effects on progenitor cell proliferation in intact E8 and E12 developing retina. The NPE cells had low levels of the Cl-transporter KCC2 compared to the mature retina, suggesting a depolarising role for the GABA(A) receptors. Treatment with KCl, which is known to depolarise membranes, prevented some of the decreased proliferation caused by inhibition of the GABA(A) receptors. This supported the depolarising role for the GABA(A) receptors. Inhibition of L-type voltage-gated Ca2+ channels (VGCCs) reduced the proliferation in the same way as inhibition of the GABA(A) receptors. Inhibition of the channels increased the expression of the cyclin-dependent kinase inhibitor p27(KIP1), along with the reduced proliferation. These results are consistent with that when the membrane potential indirectly regulates cell proliferation with hyperpolarisation of the membrane potential resulting in decreased cell division. The increased expression of p27(KIP1) after inhibition of either the GABA(A) receptors or the L-type VGCCs suggests a link between the GABA(A) receptors, membrane potential, and intracellular Ca2+ in regulating the cell cycle. 

Place, publisher, year, edition, pages
2012. Vol. 7, no 5, e36874- p.
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-172512DOI: 10.1371/journal.pone.0036874ISI: 000305336100070OAI: oai:DiVA.org:uu-172512DiVA: diva2:514813
Available from: 2012-04-11 Created: 2012-04-10 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Role of GABA and GABAA Channels in T lymphocytes and Stem cells
Open this publication in new window or tab >>Role of GABA and GABAA Channels in T lymphocytes and Stem cells
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

GABA (gamma-aminobutyric acid) is best known for its physiological function in the central nervous system.  In the brain GABA is the main inhibitory neurotransmitter where it decreases excitability of neurons and neuronal networks.  The balance between excitation evoked by glutamate and inhibition evoked by GABA is the base from where the brain works. It is fair to say that glutamate is like the gas-pedal and GABA the brake that keeps the brain running at a normal speed.  But, it is not only in the brain that GABA is taking a part in a physiological process vital to life. GABA is present in blood and is even released in the pancreatic islets. What function GABA has in these tissues is still being examined and is the focus of this thesis. The GABA concentration in the peripheral tissues is in the submicromolar concentration range. 

The studies in this thesis support the idea that GABA reduces the proliferation and cytokine secretion from immune cells by activating high-affinity GABAA channels in the cells. In contrast, in retinal progenitor stem cells GABA promotes cell proliferation.  These studies demonstrate that the effect of GABA on proliferation is cell-type specific. The GABAA channel subunit isoforms expressed in human, mice and rats T cells differ between the species.  This interspecies variability will result in different pharmacological profile of the subtypes of GABAA channels expressed whereas the physiological process most likely is the same.  Clearly, GABA is not only a neurotransmitter molecule but is also an immunomodulator and an important signal molecule in peripheral tissues. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 768
National Category
Neurosciences Physiology
Identifiers
urn:nbn:se:uu:diva-172541 (URN)978-91-554-8348-7 (ISBN)
Public defence
2012-05-28, C4 :301, BMC, Husargatan 3, Uppsala, 13:00 (English)
Supervisors
Available from: 2012-05-07 Created: 2012-04-11 Last updated: 2012-08-01Bibliographically approved
2. Characterization of Retinal Progenitor Cells: Focus on Proliferation and the GABAA Receptor System
Open this publication in new window or tab >>Characterization of Retinal Progenitor Cells: Focus on Proliferation and the GABAA Receptor System
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

One strategy to repair an injured or degenerated retina is to stimulate the replacement of damaged or dead neurons with cells derived from endogenous stem- or progenitor cells. A successful strategy requires knowledge about how the proliferation and differentiation of the endogenous cells are regulated. In particular, this knowledge will be important in the establishment of protocols that produce sufficient numbers of specific neurons. The main aim of this thesis was to find and characterise factors regulating the proliferation and differentiation of retinal progenitor cells (RPCs) and hence, contribute to the knowledge of how to use progenitor cells for retinal repair.   

The major result in this thesis is that GABA contributes to and maintains RPC proliferation. Inhibition of GABAA receptors decreases the proliferation of non-pigmented ciliary epithelial (NPE) cells and RPCs in the intact retina. We propose that this effect is mediated through changes in the membrane potential and voltage-gated calcium channels, which in turn regulate components of the cell cycle. Furthermore, we show that one of the endogenous RPC sources, the Müller cells, consists of two subpopulations based on Pax2 expression. This is interesting because Pax2 may suppress the neurogenic potential, characterised by de-differentiation and proliferation, in Müller cells. Finally, we show that over-expression of FoxN4 induces differentiation-associated transcription factors in the developing chick retina. However, FoxN4 over-expression did not trigger differentiation of NPE cells. These results indicate that the intrinsic properties of the RPCs are determinant for FoxN4-induced differentiation.

The results presented in this thesis advance our understanding of how specific cells may be generated from different sources of RPCs. Our results show that the different sources are highly diverse in their potential to proliferate and produce neurons. GABA, Pax2 and FoxN4 may be factors to consider when designing strategies for retinal repair. However, the results indicate that the specific responses to these factors are highly associated with the specific properties of the progenitor cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 821
Keyword
Regeneration, Proliferation, Neurotransmitters, Müller cells, Differentiation, Retinal repair, Neurogenesis
National Category
Neurosciences Other Basic Medicine
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-180011 (URN)978-91-554-8489-7 (ISBN)
Public defence
2012-12-13, B41, BMC, Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Note

Doctor of Philosophy (Faculty of Medicine)

Available from: 2012-11-22 Created: 2012-08-28 Last updated: 2013-02-11Bibliographically approved

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