Cortical cells reveal APP as a regulator of GABAergic neurotransmission
Anna
Doshina1,
Florian
Gourgue1,
Michiho
Onizuka1,
Remi
Opsomer1,
Peng
Wang1,
Kunie
Ando2,
Bernadette
Tasiaux1,
Ilse
Dewachter1,
Pascal
Kienlen-Campard1,
Jean-Pierre
Brion2,
Philippe
Gailly1,
Jean-Noël
Octave1* and
Nathalie
Pierrot1
-
1
Université Catholique de Louvain, Belgium
-
2
Université Libre de Bruxelles, Belgium
Besides its involvement in the pathophysiology of Alzheimer Disease (AD), the amyloid precursor protein (APP) has been reported to modulate neuronal activity which depends on the fine tuning between excitatory and inhibitory neurotransmission. GABAergic inhibitory neurotransmission is affected by modifications in intracellular chloride concentrations regulated by Na+-K+-2Cl- cotransporter 1 (NKCC1) and neuronal K+-Cl- cotransporter 2 (KCC2), allowing entrance and efflux of chloride, respectively. Changes in NKCC1 and KCC2 expression during maturation of cortical cells induce a shift in GABAergic signaling. Here, we demonstrated that APP affects this GABA shift. Expression of APP in primary cortical cultures decreased the expression of KCC2, without modifying NKCC1. Conversely, knocking down APP increased KCC2 expression in these cultures. Furthermore, in primary cortical cultures expressing APP, GABA response was less inhibitory and less hyperpolarizing. In addition, KCC2 was also downregulated in vivo following APP expression in neonatal mouse brain. Finally, KCC2 protein levels were decreased in the brains of sporadic AD patients. Our results outline a new important role of APP in KCC2 expression regulation which could influence GABAergic neurotransmission. This information advances our understanding of the physiological function of APP and sheds light on new mechanisms that could contribute to AD pathology.
Acknowledgements
This work was supported by the Belgian Fonds pour la Recherche Scientifique (FNRS-FRS), Interuniversity Attraction Poles Programme-Belgian State-Belgian Science Policy (IAP), The Belgian Fonds de la Recherche Scientifique Médicale (FRSM), the Queen Elisabeth Medical Foundation (FMRE) and the Fondation pour la Recherche sur la Maladie d’Alzheimer (SAOFRA).
Keywords:
KCC2,
Amyloid beta-Protein Precursor,
Alzheimer’s disease,
GABAergic transmission,
NKCC1
Conference:
12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017.
Presentation Type:
Oral Presentation
Topic:
Disorders of the Nervous System
Citation:
Doshina
A,
Gourgue
F,
Onizuka
M,
Opsomer
R,
Wang
P,
Ando
K,
Tasiaux
B,
Dewachter
I,
Kienlen-Campard
P,
Brion
J,
Gailly
P,
Octave
J and
Pierrot
N
(2019). Cortical cells reveal APP as a regulator of GABAergic neurotransmission.
Front. Neurosci.
Conference Abstract:
12th National Congress of the Belgian Society for Neuroscience.
doi: 10.3389/conf.fnins.2017.94.00114
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Received:
21 Mar 2017;
Published Online:
25 Jan 2019.
*
Correspondence:
Prof. Jean-Noël Octave, Université Catholique de Louvain, Brussels, Belgium, jean-noel.octave@uclouvain.be