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Liraglutide modulates GABAergic signaling in rat hippocampal CA3 pyramidal neurons predominantly by presynaptic mechanism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.ORCID iD: 0000-0001-8279-2790
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.ORCID iD: 0000-0002-4717-1558
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.ORCID iD: 0000-0002-7116-0939
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2017 (English)In: BMC Pharmacology & Toxicology, E-ISSN 2050-6511, Vol. 18, article id 83Article in journal (Refereed) Published
Abstract [en]

Background

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain where it regulates activity of neuronal networks. The receptor for glucagon-like peptide-1 (GLP-1) is expressed in the hippocampus, which is the center for memory and learning. In this study we examined effects of liraglutide, a GLP-1 analog, on GABA signaling in CA3 hippocampal pyramidal neurons.

Methods

We used patch-clamp electrophysiology to record synaptic and tonic GABA-activated currents in CA3 pyramidal neurons in rat hippocampal brain slices.

Results

We examined the effects of liraglutide on the neurons at concentrations ranging from one nM to one μM. Significant changes of the spontaneous inhibitory postsynaptic currents (sIPSCs) were only recorded with 100 nM liraglutide and then in just ≈50% of the neurons tested at this concentration. In neurons affected by liraglutide both the sIPSC frequency and the most probable amplitudes increased. When the action potential firing was inhibited by tetrodotoxin (TTX) the frequency and amplitude of IPSCs in TTX and in TTX plus 100 nM liraglutide were similar.

Conclusions

The results demonstrate that liraglutide regulation of GABA signaling of CA3 pyramidal neurons is predominantly presynaptic and more limited than has been observed for GLP-1 and exendin-4 in hippocampal neurons.

Place, publisher, year, edition, pages
2017. Vol. 18, article id 83
Keywords [en]
GABA, GLP-1 receptor, patch-clamp, inhibitory postsynaptic and tonic currents, hippocampus, electrophysiology
National Category
Other Biological Topics Neurosciences Pharmacology and Toxicology
Research subject
Neuroscience; Pharmacology; Biology with specialization in Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-282424DOI: 10.1186/s40360-017-0191-0ISI: 000418264400001PubMedID: 29246184OAI: oai:DiVA.org:uu-282424DiVA, id: diva2:917043
Projects
Effect of metabolic hormones on GABA signalling in the hippocampus
Funder
Swedish Research CouncilThe Swedish Brain FoundationEXODIAB - Excellence of Diabetes Research in SwedenÅke Wiberg FoundationAvailable from: 2016-04-05 Created: 2016-04-05 Last updated: 2018-02-16Bibliographically approved
In thesis
1. GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator
Open this publication in new window or tab >>GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

GABA (γ-aminobutyric acid) is the main neuroinhibitory transmitter in mammalian brains.  It binds to GABA-A and GABA-B receptors. The GABA-A receptors are ligand-gated chloride channels. A variety of GABA-A receptor agonists and antagonists have been developed to study the GABA-mediated inhibition and to explore new medications. In this thesis I have examined the role of GABA in brain tumors and the effects of the metabolic hormone GLP-1 on GABAergic signaling in neurons.

I studied if GABA-A receptors subunits were expressed and formed functional ion channels in the glioblastoma cell line U3047MG. I identified the mRNA of 11, α2, α3, α5, β1, β2, β3, δ, γ3, π, θ and ρ2, out of the 19 known GABA-A subunits. Immunostaining demonstrated abundant expression of the α3 and β3 subunits. Interestingly, whole-cell GABA-activated currents were recorded in only 12% of the cells. The GABA-activated currents half-maximal concentration (EC50) was 36 µM. The currents were modulated by diazepam (1 µM) and the general anesthetics propofol (50 µM) and etomidate (EC50 = 50 nM).

GLP-1 and exendin-4 transiently enhanced the GABA-A receptor-mediated currents in CA3 neurons of the rat hippocampus. The tonic and the spontaneous inhibitory postsynaptic currents increased as compared to control in a concentration dependent manner.  The increase was related to enhanced release of GABA from the presynaptic terminals and increased insertion or affinity of GABA-A receptors in the CA3 postsynaptic neuron. In contrast to GLP-1 and exendin-4, liraglutide enhanced the currents only in a subset of the neurons and the effect was mainly mediated by presynaptic mechanisms. 

In conclusion, GABA signaling in neurons is modified by the metabolic hormone GLP-1 and its mimetics highlighting the important cross-talk that takes place between the brain and other organs. Medicines modifying GABA signaling in the brain may be important for a number of diseases.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 51
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1209
National Category
Medical and Health Sciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-282431 (URN)978-91-554-9548-0 (ISBN)
Public defence
2016-05-31, C2:301, BMC, Husargatan 3, 751 24, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-05-02 Created: 2016-04-05 Last updated: 2016-05-12

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Babateen, OmarKorol, Sergiy V.Jin, ZheBhandage, Amol K.Ahemaiti, AikeremuBirnir, Bryndis

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