Dapper Antagonist of Catenin-1 Cooperates with Dishevelled-1 during Postsynaptic Development in Mouse Forebrain GABAergic Interneurons

Synaptogenesis has been extensively studied along with dendritic spine development in glutamatergic pyramidal neurons, however synapse development in cortical interneurons, which are largely aspiny, is comparatively less well understood. Dact1, one of 3 paralogous Dact (Dapper/Frodo) family members in mammals, is a scaffold protein implicated in both the Wnt/β-catenin and the Wnt/Planar Cell Polarity pathways. We show here that Dact1 is expressed in immature cortical interneurons. Although Dact1 is first expressed in interneuron precursors during proliferative and migratory stages, constitutive Dact1 mutant mice have no major defects in numbers or migration of these neurons. However, cultured cortical interneurons derived from these mice have reduced numbers of excitatory synapses on their dendrites. We selectively eliminated Dact1 from mouse cortical interneurons using a conditional knock-out strategy with a Dlx-I12b enhancer-Cre allele, and thereby demonstrate a cell-autonomous role for Dact1 during postsynaptic development. Confirming this cell-autonomous role, we show that synapse numbers in Dact1 deficient cortical interneurons are rescued by virally-mediated re-expression of Dact1 specifically targeted to these cells. Synapse numbers in these neurons are also rescued by similarly targeted expression of the Dact1 binding partner Dishevelled-1, and partially rescued by expression of Disrupted in Schizophrenia-1, a synaptic protein genetically implicated in susceptibility to several major mental illnesses. In sum, our results support a novel cell-autonomous postsynaptic role for Dact1, in cooperation with Dishevelled-1 and possibly Disrupted in Schizophrenia-1, in the formation of synapses on cortical interneuron dendrites.     

Cardiac myoglobin deficit has evolved repeatedly in teleost fishes

Myoglobin (Mb) is the classic vertebrate oxygen-binding protein present in aerobic striated muscles. It functions principally in oxygen delivery and provides muscle with its characteristic red colour. Members of the Antarctic icefish family (Channichthyidae) are widely thought to be extraordinary for lacking cardiac Mb expression, a fact that has been attributed to their low metabolic rate and unusual evolutionary history. Here, we report that cardiac Mb deficit, associated with pale heart colour, has evolved repeatedly during teleost evolution. This trait affects both gill- and air-breathing species from temperate to tropical habitats across a full range of salinities. Cardiac Mb deficit results from total pseudogenization in three-spined stickleback and is associated with a massive reduction in mRNA level in two species that evidently retain functional Mb. The results suggest that near or complete absence of Mb-assisted oxygen delivery to heart muscle is a common facet of teleost biodiversity, even affecting lineages with notable oxygen demands. We suggest that Mb deficit may affect how different teleost species deal with increased tissue oxygen demands arising under climate change.     

Systemic delivery of an adenovirus expressing EBV-derived vIL-10 in mice infected with Schistosoma mansoni or Leishmania amazonensis: controversial effects on the development of pathological parameters.

Within the context of microorganism/host interactions, those which last over weeks are expected to be sensitive to more or less sustained and targeted immuno-intervention, such as delivery of cytokines known to operate as down-regulators of acute inflammatory processes. IL-10 has received growing attention as a potential tool in immunotherapy, due to its anti-inflammatory and immunosuppressive properties. Therefore, using two experimental models of long-term interactions between parasites and laboratory mice, we monitored some effects of the systemic delivery of an adenovirus (Ad) expressing EBV-derived IL-10 (vIL-10) designated Ad-vIL-10. We first monitored the vIL-10 serum level following intranasal, intraperitoneal, intramuscular and intravenous administration. The i. p. and i.v. delivery of Ad-vIL-10 allowed a high serum level of vIL-10 (= 100 ng/ml), the i.v. route leading to a more sustained expression (up to 3 weeks). As a first model of parasite/mouse interaction, Schistosoma mansoni/C57Bl/6 mouse was selected. Ad-vIL-10 delivery was performed 4 weeks after S. mansoni infection i.e. at the time of egg-laying, and several parameters were monitored: (i) number of adult worms in the mesenteric vein, (ii) number of eggs trapped in the liver and intestine, (iii) liver fibrosis, (iv) serum levels of egg-reactive antibody subclasses, (v) serum content of cytokines, and (vi) cytokine production in the supernatant of antigen-stimulated mesenteric lymph node cells. No apparent effect was observed, either on the different parasitological parameters or on fibrosis development at day 70 of infection. Surprisingly, a marked increase in both Th1 and Th2 type cytokines was observed in the sera of the Ad-vIL-10 injected animals, as well as in the supernatants of their Ag-stimulated mesenteric lymph node cells. Nevertheless, polarization of the humoral response towards a Th2 profile was demonstrated by an increase in the IgE level in the Ad-vIL-10-injected animals. As far as the second model is concerned, namely the Leishmania amazonensis /C57Bl6 mouse interactions, Ad-vIL-10 was delivered intravenously one day before subcutaneous injection of stationary promastigotes and footpad swelling was monitored over 110 days. Under these conditions, vIL-10 exhibited a biphasic effect, decreasing the lesion size at the early stages of infection, but leading to a more pronounced lesion size during the chronic phase. This observation suggests a deactivation of the macrophage host cells under the influence of vIL-10. The results are discussed in the context of immunotherapy and the paradoxical effects observed in immunointervention with vIL-10.     

The effect of mobbing vocalizations on risk perception in common mynas (Acridotheres tristis)

Journal of Ethology - Animals emit predator-elicited calls in response to potential predation threats. These vocalizations induce a variety of anti-predator behaviors in conspecific receivers...     

Alternative splice isoforms of small conductance calcium-activated SK2 channels differ in molecular interactions and surface levels

Small conductance Ca²⁺-sensitive potassium (SK2) channels are voltage-independent, Ca²⁺-activated ion channels that conduct potassium cations and thereby modulate the intrinsic excitability and synaptic transmission of neurons and sensory hair cells. In the cochlea, SK2 channels are functionally coupled to the highly Ca²⁺ permeant α9/10-nicotinic acetylcholine receptors (nAChRs) at olivocochlear postsynaptic sites. SK2 activation leads to outer hair cell hyperpolarization and frequency-selective suppression of afferent sound transmission. These inhibitory responses are essential for normal regulation of sound sensitivity, frequency selectivity, and suppression of background noise. However, little is known about the molecular interactions of these key functional channels. Here we show that SK2 channels co-precipitate with α9/10-nAChRs and with the actin-binding protein α-actinin-1. SK2 alternative splicing, resulting in a 3 amino acid insertion in the intracellular 3′ terminus, modulates these interactions. Further, relative abundance of the SK2 splice variants changes during developmental stages of synapse maturation in both the avian cochlea and the mammalian forebrain. Using heterologous cell expression to separately study the 2 distinct isoforms, we show that the variants differ in protein interactions and surface expression levels, and that Ca²⁺ and Ca²⁺-bound calmodulin differentially regulate their protein interactions. Our findings suggest that the SK2 isoforms may be distinctly modulated by activity-induced Ca²⁺ influx. Alternative splicing of SK2 may serve as a novel mechanism to differentially regulate the maturation and function of olivocochlear and neuronal synapses.     

In vitro assessment of the toxicity of metal compounds

A review of in vitro mutagenesis assessment of metal compounds in mammalian and nonmammalian test systems has been compiled. Prokaryotic assays are ineffective or inconsistent in their detection of most metals as mutagens, with the notable exception of hexavalent chromium. Mammalian assay systems appear to be similarly inappropriate for the screening of metal compounds based upon the limited number of studies that have employed those compounds having known carcinogenic activity. Although of limited value as screening tests for the detection of potentially carcinogenic metal compounds, the well-characterized in vitro mutagenesis systems may prove to be of significant value as a means to elucidate mechanisms of metal genotoxicity.     

Language,Reading, and Math Learning Profiles in an Epidemiological Sample of School Age Children

Dyscalculia, dyslexia, and specific language impairment (SLI) are relatively specific developmental learning disabilities in math, reading, and oral language, respectively, that occur in the context of average intellectual capacity and adequate environmental opportunities. Past research has been dominated by studies focused on single impairments despite the widespread recognition that overlapping and comorbid deficits are common. The present study took an epidemiological approach to study the learning profiles of a large school age sample in language, reading, and math. Both general learning profiles reflecting good or poor performance across measures and specific learning profiles involving either weak language, weak reading, weak math, or weak math and reading were observed. These latter four profiles characterized 70% of children with some evidence of a learning disability. Low scores in phonological short-term memory characterized clusters with a language-based weakness whereas low or variable phonological awareness was associated with the reading (but not language-based) weaknesses. The low math only group did not show these phonological deficits. These findings may suggest different etiologies for language-based deficits in language, reading, and math, reading-related impairments in reading and math, and isolated math disabilities.