Mice deficient in transmembrane prostatic acid phosphatase display increased GABAergic transmission and neurological alterations.

Heidi O Nousiainen,Usama Abo-Ramadan,Vootele Voikar,Ileana B Quintero,Annakaisa M Herrala,Anitta E Pulkka,Natalia Kulesskaya,Tomi Taira,Timo T Myöhänen,Pirkko Vihko,Heikki Rauvala,Jelena Mijatovic,Mikael Segerstråle,Tanja Kivinummi,T Petteri Piepponen

doi:10.1371/journal.pone.0097851

Abstract

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.

Highlights

There are two isoforms of prostatic acid phosphatase enzyme: secretory and transmembrane (TMPAP) [1,2] splice variants encoded by the same gene (ACPP)
Post-hoc Newman-Keuls test revealed that treatment with haloperidol increased the prepulse inhibition (PPI) of KO mice to the level of WT mice treated with saline (p = 0.48) and no difference was observed between KO and WT mice treated with haloperidol (p = 0.09)
To discern which mechanism was causing the increment in dihydroxyphenylacetic acid (DOPAC), we studied DA synthesis rate by blocking the dopadecarboxylase enzyme which converts L-dopa to DA by using NSD1015 as inhibitor, and measured the accumulation of Ldopa as an index of DA synthesis [20], and observed that the accumulation of L-DOPA was 14% higher in PAP2/2 mice, verifying augmented synthesis of DA (Fig. 3D)

Summary

Introduction

There are two isoforms of prostatic acid phosphatase enzyme: secretory (sPAP) and transmembrane (TMPAP) [1,2] splice variants encoded by the same gene (ACPP). TMPAP is a type 1 transmembrane protein with 59ectonucleotidase activity and is widely expressed in non-prostatic tissues in both sexes. TMPAP colocalizes with exosomal markers flotillin and Lamp-1 [1], is released in exosomes and interacts in prostate cells with the SNARE-associated protein snapin [3]. Snapin interacts biochemically with t-snare SNAP-25, which belongs to the presynaptic release machinery [4], and is critical for presynaptic homeostatic plasticity [5]. SNAP-25 is involved in slow clathrin-dependent endocytosis [6], and alterations in clathrin-mediated endocytosis and clathrindependent membrane and protein trafficking have been hypothesized as core pathophysiological mechanisms in neuropsychiatric disorders such as schizophrenia and bipolar disorders [7]. When exosomes were described for the first time, it was shown that exosomes display 59-ectonucleotidase activity [8]

Methods

Results

Conclusion