Although the involvement of pathological tau in neurodegenerative dementias is indisputable, its physiological roles have remained elusive in part because its abrogation has been reported without overt phenotypes in mice and Drosophila. This was addressed using the recently described Drosophila tau KO and Mi{MIC} mutants and focused on molecular and behavioral analyses. Initially, we show that Drosophila tau (dTau) loss precipitates dynamic cytoskeletal changes in the adult Drosophila CNS and translation upregulation. Significantly, we demonstrate for the first time distinct roles for dTau in adult mushroom body (MB)-dependent neuroplasticity as its downregulation within ␣Ј␤Јneurons impairs habituation. In accord with its negative regulation of translation, dTau loss specifically enhances protein synthesis-dependent long-term memory (PSD-LTM), but not anesthesia-resistant memory. In contrast, elevation of the protein in the MBs yielded premature habituation and depressed PSD-LTM. Therefore, tau loss in Drosophila dynamically alters brain cytoskeletal dynamics and profoundly affects neuronal proteostasis and plasticity.

Habituation is the adaptive behavioral outcome of processes engaged in timely devaluation of non-reinforced repetitive stimuli, but the neuronal circuits and molecular mechanisms that underlie them are not well understood. To gain insights into these processes we developed and characterized a habituation assay to repetitive footshocks in mixed sex Drosophila groups and demonstrated that acute neurotransmission from adult ␣/␤ mushroom body (MB) neurons prevents premature stimulus devaluation. Herein we demonstrate that activity of the non-receptor tyrosine kinase dBtk protein is required within these neurons to prevent premature habituation. Significantly, we also demonstrate that the complementary process of timely habituation to the repetitive stimulation is facilitated by ␣Ј/␤Ј MB neurons and also requires dBtk activity. Hence our results provide initial insights into molecular mechanisms engaged in footshock habituation within distinct MB neurons. Importantly, dBtk attenuation specifically within ␣Ј/␤Ј neurons leads to defective habituation, which is readily reversible by administration of the antipsychotics clozapine and risperidone suggesting that the loss of the kinase may dysregulate monoamine receptors within these neurons, whose activity underlies the failure to habituate.

In addition to mechanisms promoting protein-synthesis-dependent long-term memory (PSD-LTM), the process appears to also be specifically constrained. We present evidence that the highly conserved receptor tyrosine kinase dAlk is a novel PSD-LTM attenuator in Reduction of dAlk levels in adult α/β mushroom body (MB) neurons during conditioning elevates LTM, whereas its overexpression impairs it. Unlike other memory suppressor proteins and miRNAs, dAlk within the MBs constrains PSD-LTM specifically but constrains learning outside the MBs as previously shown. Dendritic dAlk levels rise rapidly in MB neurons upon conditioning, a process apparently controlled by the 3'UTR of its mRNA, and interruption of the 3'UTR leads to enhanced LTM. Because its activating ligand Jeb is dispensable for LTM attenuation, we propose that postconditioning elevation of dAlk within α/β dendrites results in its autoactivation and constrains formation of the energy costly PSD-LTM, acting as a novel memory filter. In addition to the widely studied molecular mechanisms promoting protein-synthesis-dependent long-term memory (PSD-LTM), recent discoveries indicate that the process is also specifically constrained. We describe a role in PSD-LTM constraint for the first receptor tyrosine kinase (RTK) involved in olfactory memory in Unlike other memory suppressor proteins and miRNAs, dAlk limits specifically PSD-LTM formation as it does not affect 3 h, or anesthesia-resistant memory. Significantly, we show conditioning-dependent dAlk elevation within the mushroom body dendrites and propose that its local abundance may activate its kinase activity, to mediate imposition of PSD-LTM constraints through yet unknown mechanisms.

BACKGROUND: Statistical analyses in human populations have associated limited food availability during development with increased longevity of next generations. In support, recent findings in Caenorhabditis elegans revealed nutritional effects on transgenerational longevity.OBJECTIVES: In this study we tested the effect of nutrition on longevity of future generations in Drosophila and whether this is sex-specific.METHODS: We reared male larvae and adults of Drosophila under different food conditions and performed lifespan analyses in F2 generation.RESULTS: Grandsons of males which experienced starvation through larval stages were long-lived and grandsons of well fed larvae were short lived, in two Drosophila strains. In one strain, the nutritional effect on transgenerational longevity was transmitted through male line. Interestingly, we find that dietary restriction in adult males is the main nutritional condition affecting lifespan of grandsons.CONCLUSIONS: Our findings suggest that nutritional regulation of transgenerational longevity is evolutionarily conserved and developmental stage – dependent in Drosophila.