In this project we studied the effect of IIS on learning and memory in C. elegans and Drosophila melanogaster. IIS mutants had improved learning capacity, through FOXO factor, but declined LTAM, through reduced TOR activity. We found that acute TOR inhibition reduced LTAM through S6Kinase de-activation and serotonergic cells-specific autophagy induction through atg1 upregulation. Interestingly, autophagy induction affected both memory and mood, making them less afraid, with higher exploratory activated and more motivated to move towards the light. This effect was abrogated by autophagy inhibition specifically in the ellipsoid bodies, a brain area that has been associated with LTAM formation. To elucidate the neuronal network through which autophagy exerts its effects on behaviour and cognition, we performed biochemical and genetic analysis that revealed serotonin 5HT7 receptor as the mediator of autophagy-triggered mood and cognitive alterations. Downregulation of 5ht7 in nmda-specific cells, which reside mainly in ellipsoid bodies, caused a depression-like phenotype, but unaltered memory performance. Rapamycin treated flies exhibited decreased glutamatergic activity, possibly through increased endocytosis of NMDA2 receptor, which is mainly expressed in ellipsoid bodies and has been largely implicated in LTAM formation. We believe that 5HT7 might regulate levels of NMDA2 endocytosis and, through this, affects mood and memory. Moreover, upregulation of 5ht7 in nmda expressing cells caused in flies a phenotype similar to upregulated serotonergic autophagy and rapamycin treatment. In support, developmental defects triggered by paneuronal autophagy upregulation were recapitulated by dopaminergic specific upregulation of 5ht7. Hence, we believe that we have found a novel mechanism through which autophagy coordinates mood and cognition via 5HT7 receptor and NMDA2 receptor. Interestingly, this mechanism seems to be evolutionarily conserved in worms, where mutants for ser-2, a highly homologous to 5ht7 receptor serotonin receptor gene, have increased autophagy and they are resistant to rapamycin treatment mediated memory decline and lifespan enhancement. Finally, we find that mitophagy inducer Urolithin A inhibits learning decline through aging. However we did not manage to detect any neuronal morphological alteration in aged Urolithin A treated worms, compared to the controls.
The above results were presented (oral presentation) at the international EMBO Workshop on Molecular Neurobiology, 8-12 May 2018, Fodele, Crete, Greece.
