Extracellular nucleotides are believed to be important regulators of ion transport in epithelial tissues as a result of their ability to activate cell surface receptors. Although numerous receptors that bind nucleotides have been identified, the complexity of this receptor family, combined with the lack of pharmacological agents specific for these receptors, has made the assignment of particular receptors and ligands to physiological responses difficult. Because ATP and UTP appear equipotent and equieffective in regulating ion transport in many epithelia, we tested the hypothesis that the P2Y 2 receptor (P2Y 2 -R) subtype mediates these responses in mouse epithelia, with gene targeting techniques. Mice with the P2Y 2 -R locus targeted and inactivated (P2Y 2 -R(؊/؊)) were generated, airways (trachea), gallbladder, and intestines (jejunum) excised, and Cl ؊ secretory responses to luminal nucleotide additions measured in Ussing chambers. Comparison of P2Y 2 -R(؉/؉) with P2Y 2 -R(؊/؊) mice revealed that P2Y 2 -R mediated most (>85-95%) nucleotide-stimulated Cl ؊ secretion in trachea, about 50% of nucleotide responses in the gallbladder, and none of the responses in the jejunum. Dose-effect relationships for nucleotides in tissues from P2Y 2 -R(؊/؊) mice suggest that the P2Y 6 -R regulates ion transport in gallbladder and to a lesser extent trachea, whereas P2Y 4 and/or unidentified receptor(s) regulate ion transport in jejunum. We conclude that the P2Y 2 receptor is the dominant P2Y purinoceptor that regulates airway epithelial ion transport, whereas other P2Y receptor subtypes are relatively more important in other nonrespiratory epithelia.Metabotropic (G protein-coupled) P2Y receptors are expressed in epithelia and regulate epithelial ion transport and, consequently, have become potential targets for drug therapy of diseases that reflect abnormal epithelial ion transport (1). Of particular interest in this context is cystic fibrosis (CF), 1 a disease that reflects widespread defects in epithelial ion transport due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) (2). However, the spectrum of epithelia affected by this disease (e.g. airway, gallbladder, and intestine), the diversity of P2Y receptor subtypes (3), and the absence of selective reagents to define which P2Y receptor subtypes regulate ion transport have made it difficult to initiate therapeutic programs to target specific purinoceptors in these tissues.The strongest evidence for a role for P2 receptors in the regulation of ion transport emanates from studies of airway epithelia. Recent reports indicate that extracellular triphosphate nucleotides regulate many of the airway ion transport paths, including slowing Na ϩ absorption (4) and stimulating Cl Ϫ and K ϩ secretion (5, 6). Pharmacological studies in the human airway epithelial cell line CF/T43 have demonstrated that UTP and ATP are equipotent and cross-desensitize in promoting phospholipase C activity, leading to the hypothesis that the P2Y 2 receptor (P2Y 2 -R) is the d...
Background Social dysfunction is a hallmark symptom of schizophrenia which commonly precedes the onset of psychosis. It is unclear if social symptoms in clinical high-risk patients reflect depressive symptoms or are a manifestation of negative symptoms. Method We compared social function scores on the Social Adjustment Scale-Self Report between 56 young people (aged 13–27 years) at clinical high risk for psychosis and 22 healthy controls. The cases were also assessed for depressive and ‘prodromal’ symptoms (subthreshold positive, negative, disorganized and general symptoms). Results Poor social function was related to both depressive and negative symptoms, as well as to disorganized and general symptoms. The symptoms were highly intercorrelated but linear regression analysis demonstrated that poor social function was primarily explained by negative symptoms within this cohort, particularly in ethnic minority patients. Conclusions Although this study demonstrated a relationship between social dysfunction and depressive symptoms in clinical high-risk cases, this association was primarily explained by the relationship of each of these to negative symptoms. In individuals at heightened risk for psychosis, affective changes may be related to a progressive decrease in social interaction and loss of reinforcement of social behaviors. These findings have relevance for potential treatment strategies for social dysfunction in schizophrenia and its risk states and predict that antidepressant drugs, cognitive behavioral therapy and/or social skills training may be effective.
Transformations in affective and social behaviors, many of which involve amygdalar circuits, are hallmarks of adolescence in many mammalian species. In this study, using the rat as a model, we provide the first evidence that afferents of the basal amygdala (BA) undergo significant structural remodeling during adolescence. We used quantitative tract-tracing and gene expression profiling methods to characterize changes in the medial prefrontal cortical (mPFC) inputs to the BA across ages analogous to the late juvenile period [postnatal day (P) 25], late adolescence (P45), and adulthood (P90) in the rat. As assessed after deposition of Fluorogold into the BA, the number of BA-projecting neurons in the mPFC remained stable between P25 and P45 but decreased by about 50% between P45 and P90. Anterograde tract tracing with biotin dextran amine deposits centered in the ventral prelimbic cortex revealed that, during this period, the density of mPFC-derived axon terminals in the BA also decrease significantly, an effect particularly evident in the dorsal basolateral nucleus. Within the BA, there were also highly significant changes in gene expression indicative of neurite or synaptic plasticity, most notably in the Ras/GTPase superfamily, and in pathways that regulate cytoskeletal dynamics and steroid synthesis/lipid metabolism. These data provide convergent evidence that mPFC inputs to the BA are pruned during late adolescence or early adulthood. Moreover, the structural remodeling within these afferents may be accompanied by significant changes in neurite plasticity within the BA.
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