Lhx6 regulates the migration of cortical interneurons from the ventral telencephalon but does not specify their GABA phenotype

The LIM homeodomain family of transcription factors is involved in many processes in the developing CNS, ranging from cell fate specification to connectivity. A member of this family of transcription factors, lhx6, is expressed in the medial ganglionic eminence(MGE) of the ventral telencephalon, where the vast majority of cortical interneurons are generated. Its expression in the GABA-containing MGE cells that migrate to the cortex suggests that this gene uniquely or in combination with other transcription factors may play a role in the neurochemical identity and migration of these neurons. We performed loss of function studies for lhx6 in mouse embryonic day 13.5 brain slices and dissociated MGE neuronal cultures using Lhx6-targeted small interfering RNA produced by a U6 promoter-driven vector. We found that silencing lhx6 impeded the tangential migration of interneurons into the cortex, although it did not obstruct their dispersion within the ganglionic eminence. Blocking lhx6 expression in dissociated MGE cultured neurons did not interfere with the production of GABA or its synthesizing enzyme. These results indicate that lhx6, unlike the closely related member lhx7, does not regulate neurotransmitter choice in interneurons but plays an important role in their migration from the ventral telencephalon to the neocortex

Amyloid-β acts as a regulator of neurotransmitter release disrupting the interaction between synaptophysin and VAMP2.

BACKGROUND: It is becoming increasingly evident that deficits in the cortex and hippocampus at early stages of dementia in Alzheimer's disease (AD) are associated with synaptic damage caused by oligomers of the toxic amyloid-β peptide (Aβ42). However, the underlying molecular and cellular mechanisms behind these deficits are not fully understood. Here we provide evidence of a mechanism by which Aβ42 affects synaptic transmission regulating neurotransmitter release. METHODOLOGY/FINDINGS: We first showed that application of 50 nM Aβ42 in cultured neurones is followed by its internalisation and translocation to synaptic contacts. Interestingly, our results demonstrate that with time, Aβ42 can be detected at the presynaptic terminals where it interacts with Synaptophysin. Furthermore, data from dissociated hippocampal neurons as well as biochemical data provide evidence that Aβ42 disrupts the complex formed between Synaptophysin and VAMP2 increasing the amount of primed vesicles and exocytosis. Finally, electrophysiology recordings in brain slices confirmed that Aβ42 affects baseline transmission. CONCLUSIONS/SIGNIFICANCE: Our observations provide a necessary and timely insight into cellular mechanisms that underlie the initial pathological events that lead to synaptic dysfunction in Alzheimer's disease. Our results demonstrate a new mechanism by which Aβ42 affects synaptic activity

Synapsin I phosphorylation is dysregulated by beta-amyloid oligomers and restored by valproic acid

Alzheimer’s disease is the most prevalent form of dementia in the elderly but the precise causal mechanisms are still not fully understood. Growing evidence supports a significant role for Aβ42 oligomers in the development and progression of Alzheimer’s. For example, intracellular soluble Aβ oligomers are thought to contribute to the early synaptic dysfunction associated with Alzheimer’s disease, but the molecular mechanisms underlying this effect are still unclear. Here, we identify a novel mechanism that contributes to our understanding of the reported synaptic dysfunction. Using primary rat hippocampal neurons exposed for a short period of time to Aβ42 oligomers, we show a disruption in the activity-dependent phosphorylation cycle of SynapsinI at Ser9. SynapsinI is a pre-synaptic protein that responds to neuronal activity and regulates the availability of synaptic vesicles to participate in neurotransmitter release. Phosphorylation of SynapsinI at Ser9, modulates its distribution and interaction with synaptic vesicles. Our results show that in neurons exposed to Aβ42 oligomers, the levels of phosphorylated Ser9 of SynapsinI remain elevated during the recovery period following neuronal activity. We then investigated if this effect could be targeted by a putative therapeutic regime using valproic acid (a short branch-chained fatty acid) that has been proposed as a treatment for Alzheimer’s disease. Exposure of Aβ42 treated neurons to valproic acid, showed that it restores the physiological regulation of SynapsinI after depolarisation. Our data provide a new insight on Aβ42-mediated pathology in Alzheimer’s disease and supports the use of Valproic acid as a possible pharmaceutical intervention for the treatment of Alzheimer’s disease

Gene regulatory network subcircuit controlling a dynamic spatial pattern of signaling in the sea urchin embryo

We dissect the transcriptional regulatory relationships coordinating the dynamic expression patterns of two signaling genes, wnt8 and delta, which are central to specification of the sea urchin embryo endomesoderm. cis-Regulatory analysis shows that transcription of the gene encoding the Notch ligand Delta is activated by the widely expressed Runx transcription factor, but spatially restricted by HesC-mediated repression through a site in the delta 5′UTR. Spatial transcription of the hesC gene, however, is controlled by Blimp1 repression. Blimp1 thus represses the repressor of delta, thereby permitting its transcription. The blimp1 gene is itself linked into a feedback circuit that includes the wnt8 signaling ligand gene, and we showed earlier that this circuit generates an expanding torus of blimp1 and wnt8 expression. The finding that delta expression is also controlled at the cis-regulatory level by the blimp1-wnt8 torus-generating subcircuit now explains the progression of Notch signaling from the mesoderm to the endoderm of the developing embryo. Thus the specific cis-regulatory linkages of the gene regulatory network encode the coordinated spatial expression of Wnt and Notch signaling as they sweep outward across the vegetal plate of the embryo

Electrochemical Antigenic Sensor for the Diagnosis of Chronic Q Fever

In this work, we report the development of an impedimetric biosensor for the direct, quick, and easy diagnosis of chronic Q fever. The biosensor is based on highly sensitive antigens that can selectively recognize antibodies against Coxiella burnetii. The biosensor is based on the immobilization of antigens onto a gold electrode using the EDC/NHS immobilization methodology. The detection is performed by impedance spectroscopy that monitors specific frequencies which provide the maximum sensitivity for the biosensor. Q fever antibodies that are present in the sera of patients interact selectively with the biosensor antigens, thereby altering the impedance of the biosensor surfaceand generating a large impedance change within a few seconds. The biosensor allows for the specific serological detection of chronic Q fever, while the developed system can also be modified for the detection of other biomarkers, such as the ones against acute Q fever

Neuronal migration and ventral subtype identity in the telencephalon depend on SOX1

Little is known about the molecular mechanisms and intrinsic factors that are responsible for the emergence of neuronal subtype identity. Several transcription factors that are expressed mainly in precursors of the ventral telencephalon have been shown to control neuronal specification, but it has been unclear whether subtype identity is also specified in these precursors, or if this happens in postmitotic neurons, and whether it involves the same or different factors. SOX1, an HMG box transcription factor, is expressed widely in neural precursors along with the two other SOXB1 subfamily members, SOX2 and SOX3, and all three have been implicated in neurogenesis. SOX1 is also uniquely expressed at a high level in the majority of telencephalic neurons that constitute the ventral striatum (VS). These neurons are missing in Sox1-null mutant mice. In the present study, we have addressed the requirement for SOX1 at a cellular level, revealing both the nature and timing of the defect. By generating a novel Sox1-null allele expressing β-galactosidase, we found that the VS precursors and their early neuronal differentiation are unaffected in the absence of SOX1, but the prospective neurons fail to migrate to their appropriate position. Furthermore, the migration of non-Sox1-expressing VS neurons (such as those expressing Pax6) was also affected in the absence of SOX1, suggesting that Sox1-expressing neurons play a role in structuring the area of the VS. To test whether SOX1 is required in postmitotic cells for the emergence of VS neuronal identity, we generated mice in which Sox1 expression was directed to all ventral telencephalic precursors, but to only a very few VS neurons. These mice again lacked most of the VS, indicating that SOX1 expression in precursors is not sufficient for VS development. Conversely, the few neurons in which Sox1 expression was maintained were able to migrate to the VS. In conclusion, Sox1 expression in precursors is not sufficient for VS neuronal identity and migration, but this is accomplished in postmitotic cells, which require the continued presence of SOX1. Our data also suggest that other SOXB1 members showing expression in specific neuronal populations are likely to play continuous roles from the establishment of precursors to their final differentiation

Open-Gated pH Sensor Fabricated on an Undoped-AlGaN/GaN HEMT Structure

The sensing responses in aqueous solution of an open-gated pH sensor fabricated on an AlGaN/GaN high-electron-mobility-transistor (HEMT) structure are investigated. Under air-exposed ambient conditions, the open-gated undoped AlGaN/GaN HEMT only shows the presence of a linear current region. This seems to show that very low Fermi level pinning by surface states exists in the undoped AlGaN/GaN sample. In aqueous solution, typical current-voltage (I-V) characteristics with reasonably good gate controllability are observed, showing that the potential of the AlGaN surface at the open-gated area is effectively controlled via aqueous solution by the Ag/AgCl gate electrode. The open-gated undoped AlGaN/GaN HEMT structure is capable of distinguishing pH level in aqueous electrolytes and exhibits linear sensitivity, where high sensitivity of 1.9 mA/pH or 3.88 mA/mm/pH at drain-source voltage, VDS = 5 V is obtained. Due to the large leakage current where it increases with the negative gate voltage, Nernstian like sensitivity cannot be determined as commonly reported in the literature. This large leakage current may be caused by the technical factors rather than any characteristics of the devices. Surprisingly, although there are some imperfections in the device preparation and measurement, the fabricated devices work very well in distinguishing the pH levels. Suppression of current leakage by improving the device preparation is likely needed to improve the device performance. The fabricated device is expected to be suitable for pH sensing applications