Pharmacological And Genetic Reversal Of Age-Dependent Cognitive Deficits Attributable To Decreased Presenilin Function

Alzheimer\u27s disease (AD) is the leading cause of cognitive loss and neurodegeneration in the developed world. Although its genetic and environmental causes are not generally known, familial forms of the disease (FAD) are attributable to mutations in a single copy of the Presenilin (PS) and amyloid precursor protein genes. The dominant inheritance pattern of FAD indicates that it may be attributable to gain or change of function mutations. Studies of FAD-linked forms of presenilin (psn) in model organisms, however, indicate that they are loss of function, leading to the possibility that a reduction in PS activity might contribute to FAD and that proper psn levels are important for maintaining normal cognition throughout life. To explore this issue further, we have tested the effect of reducing psn activity during aging in Drosophila melanogaster males. We have found that flies in which the dosage of psn function is reduced by 50% display age-onset impairments in learning and memory. Treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium during the aging process prevented the onset of these deficits, and treatment of aged flies reversed the age-dependent deficits. Genetic reduction of Drosophila metabotropic glutamate receptor (DmGluRA), the inositol trisphosphate receptor (InsP(3)R), or inositol polyphosphate 1-phosphatase also prevented these age-onset cognitive deficits. These findings suggest that reduced psn activity may contribute to the age-onset cognitive loss observed with FAD. They also indicate that enhanced mGluR signaling and calcium release regulated by InsP(3)R as underlying causes of the age-dependent cognitive phenotypes observed when psn activity is reduced

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS

Argonaute2 Suppresses Drosophila Fragile X Expression Preventing Neurogenesis and Oogenesis Defects

Fragile X Syndrome is caused by the silencing of the Fragile X Mental Retardation gene (FMR1). Regulating dosage of FMR1 levels is critical for proper development and function of the nervous system and germ line, but the pathways responsible for maintaining normal expression levels are less clearly defined. Loss of Drosophila Fragile X protein (dFMR1) causes several behavioral and developmental defects in the fly, many of which are analogous to those seen in Fragile X patients. Over-expression of dFMR1 also causes specific neuronal and behavioral abnormalities. We have found that Argonaute2 (Ago2), the core component of the small interfering RNA (siRNA) pathway, regulates dfmr1 expression. Previously, the relationship between dFMR1 and Ago2 was defined by their physical interaction and co-regulation of downstream targets. We have found that Ago2 and dFMR1 are also connected through a regulatory relationship. Ago2 mediated repression of dFMR1 prevents axon growth and branching defects of the Drosophila neuromuscular junction (NMJ). Consequently, the neurogenesis defects in larvae mutant for both dfmr1 and Ago2 mirror those in dfmr1 null mutants. The Ago2 null phenotype at the NMJ is rescued in animals carrying an Ago2 genomic rescue construct. However, animals carrying a mutant Ago2 allele that produces Ago2 with significantly reduced endoribonuclease catalytic activity are normal with respect to the NMJ phenotypes examined. dFMR1 regulation by Ago2 is also observed in the germ line causing a multiple oocyte in a single egg chamber mutant phenotype. We have identified Ago2 as a regulator of dfmr1 expression and have clarified an important developmental role for Ago2 in the nervous system and germ line that requires dfmr1 function

Plutonic rocks of western Fiordland, New Zealand: field relations, geochemistry, correlation, and nomenclature

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The Mw 7.6 Dusky Sound Earthquake of 2009: Preliminary Report

The Mw 7.6 Dusky Sound earthquake of July 15th, 2009, was the largest magnitude earthquake in New Zealand since the devastating 1931 Hawke‟s Bay event (Ms 7.8). The earthquake was sufficiently large to generate at least a 2.3 m wave at Passage Point. Despite its large magnitude, this event resulted in relatively minimal damage when compared to worldwide events of a similar size. This can be explained as a fortunate combination of the sparse population of the area and the specific physical characteristics of the earthquake. Centroid Moment Tensor (CMT) solutions define the rupture surface as a low-angle plane and finite fault inversions confirm the slip occurred on the interface between the eastward-subducting Australian plate and overriding Pacific plate, initiating at about 30 km depth and rupturing upward and southwestward to about 15 km depth. The oceanward rupture directivity likely contributed to the lower intensity of measured ground motion than might be expected for such a large, shallow event. The amount of radiated seismic energy from the earthquake was relatively small, and far fewer landslides were triggered from this event than from the 2003 Mw 7.2 Fiordland event

Plutonic rocks of western Fiordland, New Zealand: field relations, geochemistry, correlation, and nomenclature

This paper provides a comprehensive description of the plutonic rocks of western Fiordland between Breaksea and Sutherland Sounds. The area is dominated by the Early Cretaceous Western Fiordland Orthogneiss (WFO), but also includes smaller bodies of Paleozoic and Cretaceous granitoid. Plutonic rocks of western Fiordland intrude metasediments of the Western Province, many of whose age and terrane affinities remain undefined. Paleozoic granitoids in western Fiordland include the Pandora Orthogneiss (c. 500 Ma) and widespread related sills within Paleozoic metasedimentary rocks; the All Round Pluton (c. 340 Ma); the Deas Cove Granite (c. 372 Ma); and possibly the Straight River Granite. The Pandora Orthogneiss is one of the oldest plutons yet found in the Median Batholith. Correlatives include the Jaquiery Granite Gneiss in central Fiordland and orthogneiss in Doubtful Sound. Plutonism of Ross/Delamarian age is therefore widespread in those parts of Fiordland where Cambrian or older Western Province metasedimentary rocks form basement. The All Round Pluton and Deas Cove Granite are correlatives of the S-type Ridge and A/I-type Foulwind Suites, respectively. The c. 125-116 Ma WFO includes at least seven major dioritic and monzodioritic plutons in western Fiordland, one in central Fiordland, and one in central Stewart Island. Plutons which compose the WFO are distinguished by differences in their age, petrography, structural and metamorphic histories, and geochemistry. The WFO in northern Fiordland and the correlative Walkers Pluton on Stewart Island were emplaced in the mid crust (4-9 kbar) at depths comparable with some Separation Point Suite plutons of similar age. WFO plutons in southern Fiordland were emplaced at greater depths (10-18 kbar). WFO plutons have been variably recrystallised to eclogite; omphacite-, garnet-, two-pyroxene-, and hornblende-granulite; and hornblende-amphibolite facies assemblages, reflecting different 'PTX' conditions during metamorphism of each body. Some parts of the WFO remain undeformed and unmetamorphosed. Evidence of up to c. 6 kbar loading after emplacement is limited to WFO plutons in northern Fiordland and adjacent country rocks. Extensional ductile shear zones previously shown to locally separate the WFO from adjacent rocks are discontinuous later features, commonly localised along earlier intrusive contacts between WFO plutons and metasedimentary country rocks. They do not form a regionally extensive detachment between the upper and lower plates of a metamorphic core complex. The WFO has previously been included in the Separation Point Suite since both units share a high Sr/Y (HiSY) chemistry and were emplaced at broadly the same time. However, the WFO and Separation Point Suite have distinct chemistries. Separation Point Suite rocks generally contain greater Sr, Na, and Al, and have lower Sr/Rb ratios, rare earth element and Y contents, than WFO rocks with comparable amounts of SiO₂. Many aspects of the WFO chemistry (aside from its HiSY character) are similar to that of the older Darran Suite rather than the Separation Point Suite. This may reflect a greater amount of partial melting during generation of the SiO₂-poor WFO than the SiO₂-rich Separation Point Suite. Alternatively it may indicate derivation of the WFO and Separation Point Suite from different sources, albeit at depths greater than those where residual plagioclase is stable. Relatively large variations in the major element chemistry of the Separation Point Suite reflect fractionation and/or accumulation of plagioclase, whereas the more limited variability in the major element chemistry of the WFO reflects minor fractionation and/or accumulation of hornblende and/or clinopyroxene

Surface rupture displacement on the Greendale Fault during the Mw 7.1 Darfield (Canterbury) earthquake, New Zealand, and its impact on man-madestructures.

Surface rupture of the previously unrecognised Greendale Fault extended west-east for ~30 km across alluvial plains west of Christchurch, New Zealand, during the Mw 7.1 Darfield (Canterbury) earthquake of September 2010. Surface rupture displacement was predominantly dextral strike-slip, averaging ~2.5 m, with maxima of ~5 m. Vertical displacement was generally less than 0.75 m. The surface rupture deformation zone ranged in width from ~30 to 300 m, and comprised discrete shears, localised bulges and, primarily, horizontal dextral flexure. About a dozen buildings, mainly single-storey houses and farm sheds, were affected by surface rupture, but none collapsed, largely because most of the buildings were relatively flexible and resilient timber-framed structures and also because deformation was distributed over a relatively wide zone. There were, however, notable differences in the respective performances of the buildings. Houses with only lightly-reinforced concrete slab foundations suffered moderate to severe structural and non-structural damage. Three other buildings performed more favourably: one had a robust concrete slab foundation, another had a shallow-seated pile foundation that isolated ground deformation from the superstructure, and the third had a structural system that enabled the house to tilt and rotate as a rigid body. Roads, power lines, underground pipes, and fences were also deformed by surface fault rupture and suffered damage commensurate with the type of feature, its orientation to the fault, and the amount, sense and width of surface rupture deformation