Mice deficient in transmembrane prostatic acid phosphatase display increased GABAergic transmission and neurological alterations.
Prostatic acid phosphatase (PAP), the first diagnostic marker and present therapeutic target for prostate cancer, modulates nociception at the dorsal root ganglia (DRG), but its function in the central nervous system has remained unknown. We studied expression and function of TMPAP (the transmembrane isoform of PAP) in the brain by utilizing mice deficient in TMPAP (PAP-/- mice). Here we report that TMPAP is expressed in a subpopulation of cerebral GABAergic neurons, and mice deficient in TMPAP show multiple behavioral and neurochemical features linked to hyperdopaminergic dysregulation and altered GABAergic transmission. In addition to increased anxiety, disturbed prepulse inhibition, increased synthesis of striatal dopamine, and augmented response to amphetamine, PAP-deficient mice have enlarged lateral ventricles, reduced diazepam-induced loss of righting reflex, and increased GABAergic tone in the hippocampus. TMPAP in the mouse brain is localized presynaptically, and colocalized with SNARE-associated protein snapin, a protein involved in synaptic vesicle docking and fusion, and PAP-deficient mice display altered subcellular distribution of snapin. We have previously shown TMPAP to reside in prostatic exosomes and we propose that TMPAP is involved in the control of GABAergic tone in the brain also through exocytosis, and that PAP deficiency produces a distinct neurological phenotype.
Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital Laboratory, Helsinki, Finland.
Heidi O
HO
Nousiainen
Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital Laboratory, Helsinki, Finland.
Ileana B
IB
Quintero
Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Timo T
TT
Myöhänen
Neuroscience Center, University of Helsinki, Helsinki, Finland; Department of Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
Vootele
V
Voikar
Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Jelena
J
Mijatovic
Neuroscience Center, University of Helsinki, Helsinki, Finland; Department of Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
Mikael
M
Segerstråle
Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital Laboratory, Helsinki, Finland.
Annakaisa M
AM
Herrala
Neuroscience Center, University of Helsinki, Helsinki, Finland; Department of Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
Natalia
N
Kulesskaya
Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital Laboratory, Helsinki, Finland.
Anitta E
AE
Pulkka
Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Tanja
T
Kivinummi
Experimental MRI Laboratory, Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland; Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
Usama
U
Abo-Ramadan
Neuroscience Center, University of Helsinki, Helsinki, Finland; Department of Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland; Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
Tomi
T
Taira
Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
T Petteri
TP
Piepponen
Neuroscience Center, University of Helsinki, Helsinki, Finland.
Heikki
H
Rauvala
Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital Laboratory, Helsinki, Finland.
Pirkko
P
Vihko
D000135:Acid Phosphatase; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002462:Cell Membrane / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis; D059330:GABAergic Neurons / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D007527:Isoenzymes; D020547:Lateral Ventricles / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D021381:Protein Transport; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics*
D007527:Isoenzymes; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D004298:Dopamine