[Mastalgia : management and state of the art]. / Mastodynies : prise en charge et connaissances actuelles.

This article tries to facilitate the management of mastalgia. During their lifetime most women will experience breast pain. Many of them will visit a physician for this purpose, often led by the fear of cancer. However, in the absence of other clinical signs such as a lump or nipple discharge, the risk of malignancy remains low. In addition to the patient's medical history and physical examination, an imaging may be necessary. The absence of clinical or radiological abnormalities suffices to reassure patients in most cases. The management of mastalgia is based mainly on diet and life-style changes, the use of a well-suited bra and topical anti-inflammatory medication. In the case of mastalgia not responding to first line treatments, the patient should be referred to a breast-care unit.

Cet article cherche à faciliter la prise en charge des mastodynies. Au cours de leur vie, la majorité des femmes présenteront des mastodynies. Nombreuses sont celles qui consulteront leur médecin à cet égard, souvent par crainte d'un cancer. Cependant, en l'absence d'autres signes cliniques comme une masse ou un écoulement mamelonnaire, le risque de malignité reste faible. Outre l'anamnèse et l'examen clinique, une imagerie peut s'avérer nécessaire. L'absence d'anomalies cliniques ou radiologiques permet de rassurer les patientes dans la majorité des cas. Le traitement reposera essentiellement sur des mesures hygiéno-diététiques, le port d'un soutien-gorge adapté et l'utilisation d'anti-inflammatoires topiques. En cas de mastodynies invalidantes et réfractaires aux anti-inflammatoires, la patiente devra être adressée pour un suivi spécialisé.

Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2.

Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αß(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.

Behavioral and synaptic plasticity are impaired upon lack of the synaptic protein SAP47.

The synapse-associated protein of 47 kDa (SAP47) is a member of a phylogenetically conserved gene family of hitherto unknown function. In Drosophila, SAP47 is encoded by a single gene (Sap47) and is expressed throughout all synaptic regions of the wild-type larval brain; specifically, electron microscopy reveals anti-SAP47 immunogold labeling within 30 nm of presynaptic vesicles. To analyze SAP47 function, we used the viable and fertile deletion mutant Sap47(156), which suffers from a 1.7 kb deletion in the regulatory region and the first exon. SAP47 cannot be detected by either immunoblotting or immunohistochemistry in Sap47(156) mutants. These mutants exhibit normal sensory detection of odorants and tastants as well as normal motor performance and basic neurotransmission at the neuromuscular junction. However, short-term plasticity at this synapse is distorted. Interestingly, Sap47(156) mutant larvae also show a 50% reduction in odorant-tastant associative learning ability; a similar associative impairment is observed in a second deletion allele (Sap47(201)) and upon reduction of SAP47 levels using RNA interference. In turn, transgenically restoring SAP47 in Sap47(156) mutant larvae rescues the defect in associative function. This report thus is the first to suggest a function for SAP47. It specifically argues that SAP47 is required for proper behavioral and synaptic plasticity in flies-and prompts the question whether its homologs are required for proper behavioral and synaptic plasticity in other species as well.

The Drosophila homologue of tubulin-specific chaperone E-like protein is required for synchronous sperm individualization and normal male fertility.

The tubulin-specific chaperone E-like protein (TBCEL or E-like) of vertebrates shows sequence homology to TBCE, a component of the multimolecular complex required for tubulin heterodimer formation in all eukaryotic cells. TBCEL apparently serves more specific functions, as it is found only in animals. At the cellular level, TBCEL plays a role as a regulator of tubulin stability. It is strongly expressed in human testes, but its systemic function is not known. The gene CG12214 codes for the Drosophila homologue of the vertebrate TBCEL protein. Here we show that disruption of the Drosophila Tbcel gene causes defects in spermatid individualixation, which leads to dispersed migration of F-actin-rich investment cones. Mutations affecting the Tbcel gene cause strong reduction in male, but not female, fertility. However, mature sperm function apparently is not impaired. We generated polyclonal antisera against TBCEL to study its localization and distribution in Drosophila tissues. Immunostainings of wild-type and null mutant testes demonstrated that TBCEL is localized in testes, presumably associated with axoneme bundles prior to spermatid individualization. Molecular analysis of the transposon insertion site in the mutant mulet (mlt), for which male sterility and sperm individualization defects have previously been described, demonstrates that the mlt P-element insertion resides in the Tbcel gene. Our results show that loss of TBCEL in Drosophila is compatible with viability and normal female fertility but causes reduced male fertility. We conclude that Drosophila TBCEL is strongly expressed in testes and plays an important role in sperm individualization during spermatogenesis. The high level of Tbcel mRNA in human testes suggests a general role of TBCEL in animal spermatogenesis. However, Western blots and courtship analysis suggest that TBCEL may have additional functions in the nervous system of Drosophila that could contribute to the observed reduced male fertility. These functions now have to be investigated.

Tubulin-binding cofactor E-like (TBCEL), the protein product of the mulet gene, is required in the germline for the regulation of inter-flagellar microtubule dynamics during spermatid individualization.

Individual sperm cells are resolved from a syncytium during late step of spermiogenesis known as individualization, which is accomplished by an Individualization Complex (IC) composed of 64 investment cones. mulet encodes Tubulin-binding cofactor E-like (TBCEL), suggesting a role for microtubule dynamics in individualization. Indeed, a population of ∼100 cytoplasmic microtubules fails to disappear in mulet mutant testes during spermatogenesis. This persistence, detected using epi-fluorescence and electron microscopy, suggests that removal of these microtubules by TBCEL is a prerequisite for individualization. Immunofluorescence reveals TBCEL expression in elongated spermatid cysts. In addition, testes from mulet mutant males were rescued to wild type using tubulin-Gal4 to drive TBCEL expression, indicating that the mutant phenotype is caused by the lack of TBCEL. Finally, RNAi driven by bam-GAL4 successfully phenocopied mulet, confirming that mulet is required in the germline for individualization. We propose a model in which the cytoplasmic microtubules serve as alternate tracks for investment cones in mulet mutant testes.This article has an associated First Person interview with the first author of the paper.

Salt processing in larval Drosophila: choice, feeding, and learning shift from appetitive to aversive in a concentration-dependent way.

Sodium and chloride need to be ingested and cannot be stored. Therefore, choice of habitat and diet as related to NaCl needs to be tightly regulated. We thus expect that the behavioral effects of salt are organized according to its concentration. Here, we comparatively "fingerprint" the reflex releasing (in choice and feeding experiments) versus the reinforcing effects of sodium chloride ("salt") in terms of their concentration dependencies, using larval Drosophila. Qualitatively, we find that the behavioral effects of salt in all 3 assays are similar: choice, feeding, and reinforcing effect all change from appetitive to aversive as concentration is increased. Quantitatively, however, the appetitive effects for choice and feeding share their optimum at around 0.02 M, whereas the dose-response curve for the reinforcing effect is shifted by more than one order of magnitude toward higher concentrations. Interestingly, a similar shift between these 2 kinds of behavioral effect is also found for sugars (Schipanski et al. 2008). Thus, for salt and for sugar, the sensory-to-motor system is more sensitive regarding immediate, reflexive behavior than regarding reinforcement. We speculate that this may partially be due to a dissociation of the sensory pathways signaling toward either reflexive behavior or internal reinforcement.

Defective Synapse Maturation and Enhanced Synaptic Plasticity in Shank2 Δex7-/- Mice.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic etiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are used for a mechanistic understanding of ASDs and the development of therapeutic strategies. SHANKs are scaffold proteins in the postsynaptic density of mammalian excitatory synapses with proposed functions in synaptogenesis, regulation of dendritic spine morphology, and instruction of structural synaptic plasticity. In contrast to all studies so far on the function of SHANK proteins, we have previously observed enhanced synaptic plasticity in Shank2 Δex7-/- mice. In a series of experiments, we now reproduce these results, further explore the synaptic phenotype, and directly compare our model to the independently generated Shank2 Δex6-7-/- mice. Minimal stimulation experiments reveal that Shank2 Δex7-/- mice possess an excessive fraction of silent (i.e., α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, short, AMPA receptor lacking) synapses. The synaptic maturation deficit emerges during the third postnatal week and constitutes a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation, both in vivo and in vitro. A direct comparison with Shank2 Δex6-7-/- mice adds weight to the hypothesis that both mouse models show a different set of synaptic phenotypes, possibly due to differences in their genetic background. These findings add to the diversity of synaptic phenotypes in neurodevelopmental disorders and further support the supposed existence of "modifier genes" in the expression and inheritance of ASDs.

Angular velocity integration in a fly heading circuit.

Many animals maintain an internal representation of their heading as they move through their surroundings. Such a compass representation was recently discovered in a neural population in the Drosophila melanogaster central complex, a brain region implicated in spatial navigation. Here, we use two-photon calcium imaging and electrophysiology in head-fixed walking flies to identify a different neural population that conjunctively encodes heading and angular velocity, and is excited selectively by turns in either the clockwise or counterclockwise direction. We show how these mirror-symmetric turn responses combine with the neurons' connectivity to the compass neurons to create an elegant mechanism for updating the fly's heading representation when the animal turns in darkness. This mechanism, which employs recurrent loops with an angular shift, bears a resemblance to those proposed in theoretical models for rodent head direction cells. Our results provide a striking example of structure matching function for a broadly relevant computation.

Enhancing inhibitory synaptic function reverses spatial memory deficits in Shank2 mutant mice.

Autism spectrum disorders (ASDs) are a group of developmental disorders that cause variable and heterogeneous phenotypes across three behavioral domains such as atypical social behavior, disrupted communications, and highly restricted and repetitive behaviors. In addition to these core symptoms, other neurological abnormalities are associated with ASD, including intellectual disability (ID). However, the molecular etiology underlying these behavioral heterogeneities in ASD is unclear. Mutations in SHANK2 genes are associated with ASD and ID. Interestingly, two lines of Shank2 knockout mice (e6-7 KO and e7 KO) showed shared and distinct phenotypes. Here, we found that the expression levels of Gabra2, as well as of GABA receptor-mediated inhibitory neurotransmission, are reduced in Shank2 e6-7, but not in e7 KO mice compared with their own wild type littermates. Furthermore, treatment of Shank2 e6-7 KO mice with an allosteric modulator for the GABAA receptor reverses spatial memory deficits, indicating that reduced inhibitory neurotransmission may cause memory deficits in Shank2 e6-7 KO mice. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

RIM-binding protein, a central part of the active zone, is essential for neurotransmitter release.

The molecular machinery mediating the fusion of synaptic vesicles (SVs) at presynaptic active zone (AZ) membranes has been studied in detail, and several essential components have been identified. AZ-associated protein scaffolds are viewed as only modulatory for transmission. We discovered that Drosophila Rab3-interacting molecule (RIM)-binding protein (DRBP) is essential not only for the integrity of the AZ scaffold but also for exocytotic neurotransmitter release. Two-color stimulated emission depletion microscopy showed that DRBP surrounds the central Ca(2+) channel field. In drbp mutants, Ca(2+) channel clustering and Ca(2+) influx were impaired, and synaptic release probability was drastically reduced. Our data identify RBP family proteins as prime effectors of the AZ scaffold that are essential for the coupling of SVs, Ca(2+) channels, and the SV fusion machinery.