Schizophrenia as a disorder of disconnectivity

Schizophrenia is considered as a neurodevelopmental disorder with genetic and environmental factors playing a role. Animal models show that developmental hippocampal lesions are causing disconnectivity of the prefrontal cortex. Magnetic resonance imaging and postmortem investigations revealed deficits in the temporoprefrontal neuronal circuit. Decreased oligodendrocyte numbers and expression of oligodendrocyte genes and synaptic proteins may contribute to disturbances of micro- and macro-circuitry in the pathophysiology of the disease. Functional connectivity between cortical areas can be investigated with high temporal resolution using transcranial magnetic stimulation (TMS), electroencephalography (EEG), and magnetoencephalography (MEG). In this review, disconnectivity between different cortical areas in schizophrenia patients is described. The specificity and the neurobiological origin of these connectivity deficits and the relation to the symptom complex of schizophrenia and the glutamatergic and GABAergic system are discussed

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Expression of Sumoylation Deficient Nkx2.5 Mutant in Nkx2.5 Haploinsufficient Mice Leads to Congenital Heart Defects

Nkx2.5 is a cardiac specific homeobox gene critical for normal heart development. We previously identified Nkx2.5 as a target of sumoylation, a posttranslational modification implicated in a variety of cellular activities. Sumoylation enhanced Nkx2.5 activity via covalent attachment to the lysine residue 51, the primary SUMO acceptor site. However, how sumoylation regulates the activity of Nkx2.5 in vivo remains unknown. We generated transgenic mice overexpressing sumoylation deficient mutant K51R (conversion of lysine 51 to arginine) specifically in mouse hearts under the control of cardiac α-myosin heavy chain (α-MHC) promoter (K51R-Tg). Expression of the Nkx2.5 mutant transgene in the wild type murine hearts did not result in any overt cardiac phenotype. However, in the presence of Nkx2.5 haploinsufficiency, cardiomyocyte-specific expression of the Nkx2.5 K51R mutant led to congenital heart diseases (CHDs), accompanied with decreased cardiomyocyte proliferation. Also, a number of human CHDs-associated Nkx2.5 mutants exhibited aberrant sumoylation. Our work demonstrates that altered sumoylation status may underlie the development of human CHDs associated with Nkx2.5 mutants

Self-Organized Criticality in Developing Neuronal Networks

Recently evidence has accumulated that many neural networks exhibit self-organized criticality. In this state, activity is similar across temporal scales and this is beneficial with respect to information flow. If subcritical, activity can die out, if supercritical epileptiform patterns may occur. Little is known about how developing networks will reach and stabilize criticality. Here we monitor the development between 13 and 95 days in vitro (DIV) of cortical cell cultures (n = 20) and find four different phases, related to their morphological maturation: An initial low-activity state (≈19 DIV) is followed by a supercritical (≈20 DIV) and then a subcritical one (≈36 DIV) until the network finally reaches stable criticality (≈58 DIV). Using network modeling and mathematical analysis we describe the dynamics of the emergent connectivity in such developing systems. Based on physiological observations, the synaptic development in the model is determined by the drive of the neurons to adjust their connectivity for reaching on average firing rate homeostasis. We predict a specific time course for the maturation of inhibition, with strong onset and delayed pruning, and that total synaptic connectivity should be strongly linked to the relative levels of excitation and inhibition. These results demonstrate that the interplay between activity and connectivity guides developing networks into criticality suggesting that this may be a generic and stable state of many networks in vivo and in vitro

Msx1 and Msx2 are required for endothelial-mesenchymal transformation of the atrioventricular cushions and patterning of the atrioventricular myocardium

<p>Abstract</p> <p>Background</p> <p><it>Msx1 </it>and <it>Msx2</it>, which belong to the highly conserved <it>Nk </it>family of homeobox genes, display overlapping expression patterns and redundant functions in multiple tissues and organs during vertebrate development. <it>Msx1 </it>and <it>Msx2 </it>have well-documented roles in mediating epithelial-mesenchymal interactions during organogenesis. Given that both <it>Msx1 </it>and <it>Msx2 </it>are crucial downstream effectors of Bmp signaling, we investigated whether <it>Msx1 </it>and <it>Msx2 </it>are required for the Bmp-induced endothelial-mesenchymal transformation (EMT) during atrioventricular (AV) valve formation.</p> <p>Results</p> <p>While both <it>Msx1-/- </it>and <it>Msx2-/- </it>single homozygous mutant mice exhibited normal valve formation, we observed hypoplastic AV cushions and malformed AV valves in <it>Msx1-/-; Msx2-/- </it>mutants, indicating redundant functions of <it>Msx1 </it>and <it>Msx2 </it>during AV valve morphogenesis. In <it>Msx1/2 </it>null mutant AV cushions, we found decreased Bmp2/4 and <it>Notch1 </it>signaling as well as reduced expression of <it>Has2</it>, <it>NFATc1 </it>and <it>Notch1</it>, demonstrating impaired endocardial activation and EMT. Moreover, perturbed expression of chamber-specific genes <it>Anf</it>, <it>Tbx2</it>, <it>Hand1 </it>and <it>Hand2 </it>reveals mispatterning of the <it>Msx1/2 </it>double mutant myocardium and suggests functions of <it>Msx1 </it>and <it>Msx2 </it>in regulating myocardial signals required for remodelling AV valves and maintaining an undifferentiated state of the AV myocardium.</p> <p>Conclusion</p> <p>Our findings demonstrate redundant roles of <it>Msx1 </it>and <it>Msx2 </it>in regulating signals required for development of the AV myocardium and formation of the AV valves.</p