The polyamine transporter Slc18b1(VPAT) is important for both short and long time memory and for regulation of polyamine content in the brain

Robert Fredriksson,Aniruddha Todkar,Ganna Shevchenko,Pawel K Olszewski,Jonas Bergquist,Viktoria Hindlycke,Frida A Lindberg,Gaia Olivo,Smitha Sreedharan,Johan Alsiö,Klas Kullander,Diana M Ciuculete,Sahar Roshanbin,Helgi B Schiöth,Anders Eriksson,Karin Nordenankar,Anica Klockars,Åke Västermark,Sofie V Hellsten,A Hutchinson ,Ali A Moazzami ,Maria Hägglund ,Ken Cheng

doi:10.1371/journal.pgen.1008455

Abstract

SLC18B1 is a sister gene to the vesicular monoamine and acetylcholine transporters, and the only known polyamine transporter, with unknown physiological role. We reveal that Slc18b1 knock out mice has significantly reduced polyamine content in the brain providing the first evidence that Slc18b1 is functionally required for regulating polyamine levels. We found that this mouse has impaired short and long term memory in novel object recognition, radial arm maze and self-administration paradigms. We also show that Slc18b1 KO mice have altered expression of genes involved in Long Term Potentiation, plasticity, calcium signalling and synaptic functions and that expression of components of GABA and glutamate signalling are changed. We further observe a partial resistance to diazepam, manifested as significantly lowered reduction in locomotion after diazepam treatment. We suggest that removal of Slc18b1 leads to reduction of polyamine contents in neurons, resulting in reduced GABA signalling due to long-term reduction in glutamatergic signalling.

Highlights

Polyamines (PAs) are endogenous compounds and the most common PAs produced by mammalian cells are spermidine (Spd), spermine (Spm) and putrescine [1]
Polyamines are small peptides made by many different cells in the body, including cells in the brain, and by removing a gene coding for a transporter important for the release of polyamines in nerve cells of mice, we show that polyamines are important for proper function of the glutamate system
We could detect the SLC18B1 protein in the ctrl homogenate but the band was completely absent in the conditional KO (cKO) homogenate (Fig 1E)

Summary

Introduction

Polyamines (PAs) are endogenous compounds and the most common PAs produced by mammalian cells are spermidine (Spd), spermine (Spm) and putrescine [1]. Spd and Spm are produced by mammalian neurons from arginine and methionine via the rate limiting enzyme ornithine decarboxylase (ODC) [3], which is essential for embryonic development [4]. They are stored in synaptic vesicles and co-released with neurotransmitters upon depolarization and have been shown to act as neuromodulators. At low concentrations extracellular polyamines potentiate [5] the NMDA receptor and at high concentrations they act as blockers on the same receptor [6], by occupying specific binding sites. The polyamines can potentiate the kinate receptor and block the AMPA receptor upon binding to their specific sites [9]

Methods

Results

Conclusion