Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling.
Plasticity related gene-1 (PRG-1) is a brain-specific membrane protein related to lipid phosphate phosphatases, which acts in the hippocampus specifically at the excitatory synapse terminating on glutamatergic neurons. Deletion of prg-1 in mice leads to epileptic seizures and augmentation of EPSCs, but not IPSCs. In utero electroporation of PRG-1 into deficient animals revealed that PRG-1 modulates excitation at the synaptic junction. Mutation of the extracellular domain of PRG-1 crucial for its interaction with lysophosphatidic acid (LPA) abolished the ability to prevent hyperexcitability. As LPA application in vitro induced hyperexcitability in wild-type but not in LPA(2) receptor-deficient animals, and uptake of phospholipids is reduced in PRG-1-deficient neurons, we assessed PRG-1/LPA(2) receptor-deficient animals, and found that the pathophysiology observed in the PRG-1-deficient mice was fully reverted. Thus, we propose PRG-1 as an important player in the modulatory control of hippocampal excitability dependent on presynaptic LPA(2) receptor signaling.
Trimbuch
Thorsten
T
Institute of Cell Biology and Neurobiology and NeuroCure, Charité, Universitätsmedizin Berlin, Berlin, Germany.
Beed
Prateep
P
Vogt
Johannes
J
Schuchmann
Sebastian
S
Maier
Nikolaus
N
Kintscher
Michael
M
Breustedt
Jörg
J
Schuelke
Markus
M
Streu
Nora
N
Kieselmann
Olga
O
Brunk
Irene
I
Laube
Gregor
G
Strauss
Ulf
U
Battefeld
Arne
A
Wende
Hagen
H
Birchmeier
Carmen
C
Wiese
Stefan
S
Sendtner
Michael
M
Kawabe
Hiroshi
H
Kishimoto-Suga
Mika
M
Brose
Nils
N
Baumgart
Jan
J
Geist
Beate
B
Aoki
Junken
J
Savaskan
Nic E
NE
Bräuer
Anja U
AU
Chun
Jerold
J
Ninnemann
Olaf
O
Schmitz
Dietmar
D
Nitsch
Robert
R
D000818:Animals; D004569:Electroencephalography; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011509:Proteoglycans / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D008246:Lysophospholipids; D011509:Proteoglycans; D018091:Receptors, AMPA; D049368:Receptors, Lysophosphatidic Acid; D033921:Vesicular Transport Proteins; C075430:serglycin; C104722:glutamate receptor ionotropic, AMPA 2; C032881:lysophosphatidic acid