In an attempt to correlate behavioral and neuronal changes, we examined the structural and functional effects of odor exposure in Drosophila. Young adult flies were exposed to a high concentration of the selected odor, usually benzaldehyde or isoamyl acetate, for 4 d and subsequently tested for their olfactory response to a variety of odorants and concentrations. The behavioral response showed specific adaptation to the exposed odor. By contrast, olfactory transduction, as measured in electroantennograms, remained normal. In vivo volume measurements were performed on olfactory glomeruli, the anatomical and functional units involved in odor processing. Preexposed flies exhibited volume reduction of certain glomeruli, in an odor-selective manner. Of a sample of eight glomeruli measured, dorsal medial (DM) 2 and ventral (V) were affected by benzaldehyde exposure, whereas DM6 was affected by isoamyl acetate. Estimation of the number of synapses indicates that volume reduction involves synapse loss that can reach 30% in the V glomerulus of flies adapted to benzaldehyde. Additional features of odorant-induced adaptation, including concentration dependence and perdurance, also show correlation, because both effects are elicited by high odor concentrations and are long-lasting (Ͼ1 week). Finally, the dunce mutant fails to develop behavioral adaptation as well as morphological changes in the olfactory glomeruli after exposure. These neural changes thus appear to require the cAMP signaling pathway. Key words: adaptation; olfactory glomeruli; memory; synapse number; dunce; DrosophilaA striking property of nervous systems is their ability to adapt structural and functional features to the input they receive during lifetime. Behavioral changes, including learning and memory, correlate with modulation of neuronal activity that can eventually lead to changes in gene expression and synapse number (Bailey and Kandel, 1993;Martin and Kandel, 1996;Milner et al., 1998;Corriveau, 1999;Yuste and Sur, 1999). Experience-related changes are usually detected in response to complex environments, however, making it difficult to establish a direct correlation between synapse modification and storage of specific information (for review, see Moser, 1999). The brain of the insect imago undergoes experience-dependent modifications (Bulloch and Ridgway, 1989). Integration centers such as the mushroom bodies (Heisenberg, 1998) and the central complex (Davis, 1996;Strausfeld, 1999) have been well studied in this respect (Brandon and Coss, 1982;Withers et al., 1993;Durst et al., 1994;Gronenberg et al., 1996;Barth and Heisenberg, 1997;Fahrbach et al., 1998;Barth, 1999). Additional brain structures also undergo behaviordependent changes, in particular the antennal lobes (AL), the insect olfactory centers (Masson and Mustaparta, 1990). In the honeybee, shifting to new behavioral tasks in the hive is accompanied by specific AL structural changes, albeit the triggering stimulus remains unknown (Winnington et al., 1996;Sigg et al., 1997).The relevance of...

The possibility of changing the number of synapses may be an important asset in the treatment of neurological diseases. In this context, the synaptogenic role of the phosphoinositide-3-kinase (PI3K) signaling cascade has been previously demonstrated in Drosophila. This study shows that treatment with a PI3K-activating transduction peptide is able to promote synaptogenesis and spinogenesis in primary cultures of rat hippocampal neurons, as well as in CA1 hippocampal neurons in vivo. In culture, the peptide increases synapse density independently of cell density, culture age, dendritic complexity, or synapse type. The induced synapses also increase neurotransmitter release from cultured neurons. The synaptogenic signaling pathway includes PI3K-Akt. Furthermore, the treatment is effective on adult neurons, where it induces spinogenesis and enhances the cognitive behavior of treated animals in a fear-conditioning assay. These findings demonstrate that functional synaptogenesis can be induced in mature mammalian brains through PI3K activation.

Synapses are specialized communication points between neurons, and their number is a major determinant of cognitive abilities. These dynamic structures undergo developmental-and activity-dependent changes. During brain aging and certain diseases, synapses are gradually lost, causing mental decline. It is, thus, critical to identify the molecular mechanisms controlling synapse number. We show here that the levels of phosphoinositide 3 kinase (PI3K) regulate synapse number in both Drosophila larval motor neurons and adult brain projection neurons. The supernumerary synapses induced by PI3K overexpression are functional and elicit changes in behavior. Remarkably, PI3K activation induces synaptogenesis in aged adult neurons as well. We demonstrate that persistent PI3K activity is necessary for synapse maintenance. We also report that PI3K controls the expression and localization of synaptic markers in human neuroblastoma cells, suggesting that PI3K synaptogenic activity is conserved in humans. Thus, we propose that PI3K stimulation can be applied to prevent or delay synapse loss in normal aging and in neurological disorders.

The olfactory system of several holometabolous insect species undergoes anatomical changes after eclosion of the imago, following those occurring during metamorphosis. In parallel, odor experience and learning performance also evolve with age. Here, we analyze the case of adult Drosophila females. Synaptogenesis in the antennal lobe (AL) starts in late pupa and continues during the first days of adult life, at the same time as the behavioral response to odors matures. Individual olfactory glomeruli (DM6, DM2, and V) display specific growth patterns between days 1 and 12 of adult life. Experience can modify the olfactory pathway both structurally and functionally as shown by adaptation experiments. The modifications associated with this form of nonassociative learning seem to take place at a critical age. Exposure to benzaldehyde at days 2-5 of adult life, but not at 8-11, causes behavioral adaptation as well as structural changes in DM2 and V glomeruli. Altered levels in intracellular cAMP, caused by dunce and rutabaga mutants, do not affect the normal changes in glomerular size, at least at day 6 of development, but they prevent those elicited by experience, establishing a molecular difference between glomerular changes of intrinsic versus environmental origin. Taken together, these data demonstrate an imprinting-like phenomenon in the olfactory pathway of young Drosophila adults, and illustrate its glomerulus-specific dynamics.