Decreased 14-3-3 expression correlates with age-related regional reductions in CNS dopamine and motor function in the pond snail, Lymnaea.

Lindsay D Morgan,Mark S Yeoman,Martin Arundell,Aiyaz Mohammed,Andrew Overall,László Hernádi,Bhavik Anil Patel,Lucas D Bowler,Katrin Jennert‐Burtson,Danny O'Hare

doi:10.1111/ejn.15033

Abstract

Ageing is associated in many organisms with a reduction in motor movements. We have previously shown that the rate of feeding movements of the pond snail, Lymnaea, decreased with age but the underlying cause is not fully understood. Here, we show that dopamine in the cerebro-buccal complex is an important signalling molecule regulating feeding frequency in Lymnaea and that ageing is associated with a decrease in CNS dopamine. A proteomic screen of young and old CNSs highlighted a group of proteins that regulate stress responses. One of the proteins identified was 14-3-3, which can enhance the synthesis of dopamine. We show that the Lymnaea 14-3-3 family exists as three distinct isoforms. The expression of the 29kDa isoform (14-3-3Lym3) in the cerebro-buccal complex decreased with age and correlated with feeding rate. Using a 14-3-3 antagonist (R18) we were able to reduce the synthesis of L-DOPA and dopamine in ex vivo cerebro-buccal complexes. Together these data suggest that an age-related reduction in 14-3-3 can decrease CNS dopamine leading to a consequential reduction in feeding rate.

Highlights

The effects of age on the central nervous system (CNS) are to cause a progressive decline in both biochemical and physiological function (Lister & Barnes, 2009)
We have shown that 14-3-3 can regulate both L-DOPA and DA synthesis, we were unable to definitively demonstrate that the effects of R18 on L-DOPA production were through its ability to inhibit the 14-3-3Lym3 isoform as no selective inhibitors of this isoform are available
The results from this study demonstrate an overall age-related reduction in 14-3-3Lym3 expression in the CB complex of the pond snail, Lymnaea. We propose that this decrease reduces DA synthesis, by impairing the activity of the rate-limiting enzyme tyrosine hydroxylase (TH)

Summary

| INTRODUCTION

The effects of age on the central nervous system (CNS) are to cause a progressive decline in both biochemical and physiological function (Lister & Barnes, 2009). We have previously demonstrated that ageing is associated with a decrease in the rate of feeding movements in the pond snail, Lymnaea (Arundell et al, 2006) This reduction was linked to alterations in 5-hydroxytryptamine (5HT) signalling due to changes in the firing frequency of key serotonergic neurones, the cerebral giant cells (CGCs) and alterations in the strength of the connection of the CGCs with key motor neurons in the feeding circuitry (Patel et al, 2006; Yeoman et al, 2008). Lymnaea, studies have shown that dopaminergic receptor expression in molluscs decreases with age (Chandhoke et al, 2001; Stefano et al, 1982), currently the effects of age on CNS DA levels and their potential link to age-related reductions in the frequency of feeding have not been examined. This study explores the contribution that age-related changes in DA make to the previously described reduction in feeding frequency and by utilising a proteomics approach determines a novel age-dependent regulatory mechanism for DA synthesis

| METHODS

| RESULTS

Findings

| DISCUSSION

| CONCLUSIONS