Cortical cells reveal APP as a new player in the regulation of GABAergic neurotransmission.
The amyloid precursor protein (APP) modulates synaptic activity, resulting from the fine tuning of 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. Modifications 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 cortical cells decreased the expression of KCC2, without modifying NKCC1, eliciting a less inhibitory GABA response. Downregulation of KCC2 expression by APP was independent of the APP intracellular domain, but correlated with decreased expression of upstream stimulating factor 1 (USF1), a potent regulator of Slc12a5 gene expression (encoding KCC2). KCC2 was also downregulated in vivo following APP expression in neonatal mouse brain. These results argue for a key role of APP in the regulation of GABAergic neurotransmission.
Institute of Neuroscience, Université catholique de Louvain, 1200, Brussels, Belgium.
Anna
A
Doshina
Institute of Neuroscience, Université catholique de Louvain, 1200, Brussels, Belgium.
Florian
F
Gourgue
Institute of Neuroscience, Université catholique de Louvain, 1200, Brussels, Belgium.
Michiho
M
Onizuka
Institute of Neuroscience, Université catholique de Louvain, 1200, Brussels, Belgium.
Remi
R
Opsomer
Institute of Neuroscience, Université catholique de Louvain, 1200, Brussels, Belgium.
Peng
P
Wang
Laboratory of Histology and Neuropathology, Université libre de Bruxelles, 1070, Brussels, Belgium.
Kunie
K
Ando
Institute of Neuroscience, Université catholique de Louvain, 1200, Brussels, Belgium.
Bernadette
B
Tasiaux
Institute of Neuroscience, Université catholique de Louvain, 1200, Brussels, Belgium.
Ilse
I
Dewachter
Institute of Neuroscience, Université catholique de Louvain, 1200, Brussels, Belgium.
Pascal
P
Kienlen-Campard
Laboratory of Histology and Neuropathology, Université libre de Bruxelles, 1070, Brussels, Belgium.
Jean-Pierre
JP
Brion
Institute of Neuroscience, Université catholique de Louvain, 1200, Brussels, Belgium.
Philippe
P
Gailly
Institute of Neuroscience, Université catholique de Louvain, 1200, Brussels, Belgium. jean-noel.octave@uclouvain.be.
Jean-Noël
JN
Octave
Institute of Neuroscience, Université catholique de Louvain, 1200, Brussels, Belgium.
Nathalie
N
Pierrot
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology*; D005260:Female; D059330:GABAergic Neurons / Q000502:physiology*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D017208:Rats, Wistar; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000502:physiology*; D000096922:K Cl- Cotransporters
D016564:Amyloid beta-Protein Precursor; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578878:Slc12a2 protein, mouse