Mice Deficient in Transmembrane Prostatic Acid Phosphatase Display Increased GABAergic Transmission and Neurological Alterations

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.

Dietary supplementation with n-3 fatty acids from weaning limits brain biochemistry and behavioural changes elicited by prenatal exposure to maternal inflammation in the mouse model

“…The GABAergic abnormalities observed here likely contribute to the pattern of behavioural differences. For example, it is well-established that striatal GABAergic neurotransmission is involved in PPI 81 , 82 and anxiety-like behaviour. 82 …”

Transmembrane prostatic acid phosphatase (TMPAP) delays cells in G1 phase of the cell cycle

“…However, the expression of PAP in prostate cancer tissue has been shown to be reduced . The studies carried out in our PAP‐knockout mouse model showed that a deficiency in the expression of PAP leads to the development of prostate adenocarcinoma , increased acinar cell proliferation in the submandibular salivary glands (SMGs) and disturbed neurotransmitter signaling in the brain . The common characteristic amongst these organs is that the epithelial cells as well as neurons are polar secretory cells.…”

Variants in ACPP are associated with cerebrospinal fluid Prostatic Acid Phosphatase levels

“…Additional studies demonstrate ACPP is expressed in the brain and suggest that PAP plays a critical role in preventing cell proliferation, cancer cell invasion, and neurite retraction [ 11 , 12 ]. PAP’s function has critical implications in mental health diseases such as anxiety, depression, and schizophrenia [ 5 ], neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease [ 13 ], and possibly in brain cancer. Yet, little is known about ACPP’s function and regulation in the brain.…”

“…Specifically, ACPP is expressed in brain regions related to language, motor coordination, cognitive function, and self-awareness [ 4 – 7 ], suggesting it plays an important role in brain health. While PAP’s role within nervous tissue is not fully elucidated, it is known to localize in synaptic nerve endings [ 5 ] and co-localizes with SNAPIN [ 14 ], a protein that binds to SNAP-25 [ 15 ], which is associated with schizophrenia [ 16 – 19 ]. Recent studies further suggest PAP is a key cell growth regulator and potential tumor suppressor gene in the prostate [ 8 – 10 ], but PAP may have similar roles in the brain.…”

“…A study by Nousiainen et al explored PAP’s function in the brain using PAP knockout mice [ 5 ]. Their results demonstrate that PAP knockout mice have enlarged lateral ventricles, a common phenotype in movement and neurodegenerative disorders such as Alzheimer’s disease, dementias, bipolar disorder, schizophrenia, Parkinson’s disease, and Huntington’s disease [ 5 ]. They also observed increased anxiety in the mice and decreased prepulsed inhibition.…”