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All epithelia have their basal side in contact with a specialized extracellular matrix, the basement membrane (BM). During development, the BM contributes to the shaping of epithelial organs via its mechanical properties. These properties rely on two core components of the BM, collagen type IV and perlecan/HSPG2, which both interact with another core component, laminin, the initiator of BM assembly. While collagen type IV supplies the BM with rigidity to constrain the tissue, perlecan antagonizes this effect. Nevertheless, the number of organs that has been studied is still scarce, and given that epithelial tissues exhibit a wide array of shapes, their forms are bound to be regulated by distinct mechanisms. This is underscored by mounting evidence that BM composition and assembly/biogenesis is tissue-specific. Moreover, previous reports have essentially focused on the mechanical role of the BM in morphogenesis at the tissue scale, but not the cell scale. Here, we took advantage of the robust conservation of core BM proteins and the limited genetic redundancy of the Drosophila model system to address how this matrix shapes the wing imaginal disc, a complex organ comprising a squamous, a cuboidal and a columnar epithelium. With the use of a hypomorphic allele, we show that the depletion of Trol (Drosophila perlecan) affects the morphogenesis of the three epithelia, but particularly that of the squamous one. The planar surface of the squamous epithelium (SE) becomes extremely narrow, due to a function for Trol in the control of the squamous shape of its cells. Furthermore, we find that the lack of Trol impairs the biogenesis of the BM of the SE by modifying the structure of the collagen type IV lattice. Through atomic force microscopy and laser surgery, we demonstrate that Trol provides elasticity to the SE's BM, thereby regulating the mechanical properties of the SE. Moreover, we show that Trol acts via collagen type IV, since the global reduction in the trol mutant context of collagen type IV or the enzyme that cross-links its 7S -but not the enzyme that cross-links its NC1- domain substantially restores the morphogenesis of the SE. In addition, a stronger decrease in collagen type IV achieved by the overexpression of the matrix metalloprotease 2 exclusively in the BM of the SE, significantly rescues the organization of the two other epithelia. Our data thus sustain a model in which Trol counters the rigidity conveyed by collagen type IV to the BM of the SE, via the regulation of the NC1-dependant assembly of its scaffold, allowing the spreading of the squamous cells, spreading which is compulsory for the architecture of the whole organ.

Prenatal methylazoxymethanol (MAM) administration at gestational day 17 has been shown to induce in adult rats schizophrenia-like behaviours as well as morphological and/or functional abnormalities in structures such as the hippocampus, medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), consistent with human data.The aim of the present study was to further characterize the neurochemical alterations associated with this neurodevelopmental animal model of schizophrenia.We performed simultaneous measurements of locomotor activity and extracellular concentrations of glutamate, dopamine and noradrenaline in the mPFC and the NAcc of adult rats prenatally exposed to MAM or saline after acute systemic injection of a noncompetitive NMDA antagonist, MK-801 (0.1 mg/kg s.c.).A significant attenuation of the MK-801-induced increase in glutamate levels associated with a potentiation of the increase in noradrenaline concentrations was found in the mPFC of MAM-exposed rats, whereas no significant change was observed in the NAcc. MAM-exposed rats also exhibited an exaggerated locomotor hyperactivity, in line with the exacerbation of symptoms reported in schizophrenic patients after administration of noncompetitive NMDA antagonists.Given the importance of the mPFC in regulating the hyperlocomotor effect of NMDA antagonists, our results suggest that the prefrontal neurochemical alterations induced by MK-801 may sustain the exaggerated locomotor response in MAM-exposed rats.

A previous study has demonstrated that disruption of fear extinction-induced long-term potentiation (LTP) in the medial prefrontal cortex (mPFC) is associated with the return of fear responding. Given that immediate posttraining infusion of PD098059, an inhibitor of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) cascade, into the mPFC also promotes recovery of fear, we investigated whether impairment of mPFC ERK/MAPK cascade also interferes with development of extinction-related LTP in the mPFC in rats. In Experiment 1, extinction training consisting of repetitive presentations of a tone previously associated with eyelid-shock application induced LTP-like changes at hippocampal inputs to the mPFC that were evident for approximately 2 h following fear extinction. Infusion of PD098059 into the mPFC immediately after extinction training abolished training-related prefrontal LTP and impaired retention of extinction memory tested on the following day. In Experiment 2, immunoblotting assays revealed that posttraining infusion of PD098059 into the mPFC produced a significant reduction of mPFC ERK2. These data, along with previous findings, suggest that low levels of ERK2 phosphorylation in the mPFC may interfere with mechanisms of retention of extinction training. The involvement of mPFC LTP in fear extinction is discussed.

Stress has been reported to disrupt the induction of synaptic plasticity in different fimbria target structures. The aim of the present study was to investigate whether chronic mild stress may also affect synaptic plasticity in the medial prefrontal cortex, a fimbria target structure. Fimbria tetanus (100 Hz) did not produce any changes in medial prefrontal cortex synaptic efficacy in non-stressed rats. Rats exposed to chronic mild stress, however, developed significant long-term potentiation. Treatment with fluoxetine (10 mg/kg, intraperitoneal) suppressed long-term potentiation induction in the chronic mild stress group. These data demonstrate that stress not only inhibits long-term potentiation development, as often demonstrated, but can also facilitate long-term potentiation development in certain brain circuits.

Both the habenula and the nucleus accumbens, and especially the glutamatergic innervation of the latter from the hippocampus, have been hypothesized to be involved, in different ways, in the pathophysiology of cognitive disturbances in schizophrenia. Lesions of the habenula produce disturbances of memory and attention in experimental animals. As the habenular nuclei have been shown to influence the release of many neurotransmitters, both in the hippocampus and the nucleus accumbens, we examined in this study the effects of bilateral habenula lesions on the plasticity of the fimbria-nucleus accumbens pathway, by means of the long-term depression phenomenon in freely moving rats. Long-term depression, induced within the shell region of the nucleus accumbens by low-frequency stimulation of the fimbria, was exaggerated and showed greater persistence in habenula-lesioned rats compared with sham-operated animals. These results indicate that plasticity in the fimbria-nucleus accumbens pathway is altered by habenula lesions in a way similar to previously-reported effects of stress and the psychosis-provoking agent ketamine. Moreover, they strengthen the views that the habenula belongs to systems, mediating higher cognitive functions, which involve the hippocampus and the nucleus accumbens. Finally, this study suggests that dysfunction of the habenula could contribute to cognitive alterations in diseases such as schizophrenia, where the habenula is reported to exhibit exaggerated calcification.

Excitatory glutamatergic fibers from limbic structures, such as the hippocampus and the basolateral amygdala, are known to converge on the same neurons in the nucleus accumbens. We have recently shown that ketamine, at a dose (25 mg/kg) that produces psychosis-like behaviors in rats, decreases glutamatergic transmission between the hippocampus and the nucleus accumbens. Here we investigated whether ketamine also affects glutamatergic transmission between the basolateral amygdala and the nucleus accumbens. We also studied the effects of amphetamine (1.5 mg/kg), known to evoke psychosis-like behaviors in rats. We found that each drug produced a long-lasting (at least 30 min) potentiation of synaptic efficacy in the projection from the basolateral amygdala to the nucleus accumbens. However, while this synaptic potentiation developed shortly after ketamine injection (within 4 min), it occurred after a 30-min delay in rats injected with amphetamine. These data reveal, in freely behaving rats, that ketamine has a more rapid and powerful effect on projection targets of the basolateral amygdala than does amphetamine.