A preferential loss of GABAergic, symmetric synapses in epileptic foci: a quantitative ultrastructural analysis of monkey neocortex.

Previous immunocytochemical results from five monkeys with cortical focal epilepsy produced by alumina gel showed a severe decrease at seizure foci of axon terminals that contained glutamic acid decarboxylase (GAD), the synthesizing enzyme for the inhibitory neurotransmitter, GABA. These data indicated a functional loss of GABAergic terminals but did not show: whether this loss was caused by GABAergic nerve terminal degeneration or by a lack of GAD immunoreactivity within these terminals and if this loss of GABAergic terminals was selective for only this terminal type. To resolve these issues, cortical tissue from three of the five monkeys used in the previous study was reexamined using electron microscopy, and a quantitative morphological analysis of cortical structures was made to compare profiles of terminals and glia in the nonepileptic cortex with those in the focus and parafocus. The following statistically significant changes were observed: the number of axosomatic symmetric synapses with layer V pyramidal cells was decreased 80% at the focus and 50% at the parafocus; in the neuropil adjacent to these pyramidal somata, the number of terminals forming symmetric synapses was reduced 50% at the epileptic focus but was unchanged at the parafocus, while the number of asymmetric synapses was reduced 25% at the focus and 15% at the parafocus; and a 50% increase of glial profiles occurred at epileptic foci both in the neuropil and at sites apposed to pyramidal cell somata. The quantitative results also showed that terminals which form symmetric synapses had twice the number of mitochondria per terminal as those that form asymmetric synapses. Axon terminals which form symmetric synapses with somata and dendrites in the neocortex have been shown previously to contain GAD. Therefore, the large reduction in the number of symmetric synapses at epileptic foci and the increased gliosis indicate that the previously observed loss of GABAergic terminals at sites of focal epilepsy is caused by terminal degeneration. Since such terminals are reduced more severely at epileptic foci than other terminals, their loss could be the basis for seizure activity due to a preferential decrease of inhibitory function at epileptic foci. Hypoxia has been shown to cause a selective degeneration of terminals with the same morphology as GABAergic terminals in the cortex, and the basis for this loss could be related to higher physiological and/or metabolic activities of GABAergic cortical cells which may inhibit other cells tonically. The fact that increased numbers of mitochondria occur in GABAergic terminals supports this idea

Inhibitory, GABAergic nerve terminals decrease at sites of focal epilepsy.

Using an immunocytochemical method for the localization of the gamma-aminobutyric acid (GABA) synthesizing enzyme, glutamic acid decarboxylase (GAD), we have observed GABAergic nerve terminals distributed throughout all layers of normal monkey sensorimotor cortex. These terminals displayed ultrastructural characteristics that suggested that they arose from aspinous and sparsely spinous stellate neurons. In monkeys (Macaca mulatta and M. fascicularis) made epileptic by cortical application of alumina gel, a highly significant numerical decrease of GAD-positive nerve terminals occurred at sites of seizure foci indicating a functional loss of GABAergic inhibitory synapses. A loss of such inhibition at seizure foci could lead to epileptic activity of cortical pyramidal neurons

The regional economic impact of more graduates in the labour market: a “micro-to-macro” analysis for Scotland

This paper explores the system-wide impact of graduates on the regional economy. Graduates enjoy a significant wage premium, often interpreted as reflecting their greater productivity relative to non-graduates. If this is so there is a clear and direct supply-side impact of HEI activities on regional economies. We use an HEI-disaggregated computable general equilibrium model of Scotland to estimate the impact of the growing proportion of graduates in the Scottish labour force that is implied by the current participation rate and demographic change, taking the graduate wage premium in Scotland as an indicator of productivity enhancement. While the detailed results vary with alternative assumptions about the extent to which wage premia reflect productivity, they do suggest that the long-term supply-side impacts of HEIs provide a significant boost to regional GDP. Furthermore, the results suggest that the supply-side impacts of HEIs are likely to be more important than the expenditure impacts that are the focus of most HEI impact studies

Spike sorting for large, dense electrode arrays

Developments in microfabrication technology have enabled the production of neural electrode arrays with hundreds of closely spaced recording sites, and electrodes with thousands of sites are under development. These probes in principle allow the simultaneous recording of very large numbers of neurons. However, use of this technology requires the development of techniques for decoding the spike times of the recorded neurons from the raw data captured from the probes. Here we present a set of tools to solve this problem, implemented in a suite of practical, user-friendly, open-source software. We validate these methods on data from the cortex, hippocampus and thalamus of rat, mouse, macaque and marmoset, demonstrating error rates as low as 5%

Subcortical Source and Modulation of the Narrowband Gamma Oscillation in Mouse Visual Cortex

Primary visual cortex exhibits two types of gamma rhythm: broadband activity in the 30-90 Hz range and a narrowband oscillation seen in mice at frequencies close to 60 Hz. We investigated the sources of the narrowband gamma oscillation, the factors modulating its strength, and its relationship to broadband gamma activity. Narrowband and broadband gamma power were uncorrelated. Increasing visual contrast had opposite effects on the two rhythms: it increased broadband activity, but suppressed the narrowband oscillation. The narrowband oscillation was strongest in layer 4 and was mediated primarily by excitatory currents entrained by the synchronous, rhythmic firing of neurons in the lateral geniculate nucleus (LGN). The power and peak frequency of the narrowband gamma oscillation increased with light intensity. Silencing the cortex optogenetically did not abolish the narrowband oscillation in either LGN firing or cortical excitatory currents, suggesting that this oscillation reflects unidirectional flow of signals from thalamus to cortex

Systems chemistry: all in a spin

The authors thank the Leverhulme Trust for an award (RPG-2013-343) to support LC.A fundamental challenge in supramolecular systems chemistry is to engineer the emergence of complex behaviour. The collective structures of metal cyanide chains have now been interpreted in the same manner as the myriad of magnetic phases displayed by frustrated spin systems, highlighting a symbiotic approach between systems chemistry and magnetism.PostprintPeer reviewe

Local critical behaviour at aperiodic surface extended perturbation in the Ising quantum chain

The surface critical behaviour of the semi--infinite one--dimensional quantum Ising model in a transverse field is studied in the presence of an aperiodic surface extended modulation. The perturbed couplings are distributed according to a generalized Fredholm sequence, leading to a marginal perturbation and varying surface exponents. The surface magnetic exponents are calculated exactly whereas the expression of the surface energy density exponent is conjectured from a finite--size scaling study. The system displays surface order at the bulk critical point, above a critical value of the modulation amplitude. It may be considered as a discrete realization of the Hilhorst--van Leeuwen model.Comment: 13 pages, TeX file + 6 figures, epsf neede

Spin chirality on a two-dimensional frustrated lattice

The collective behavior of interacting magnetic moments can be strongly influenced by the topology of the underlying lattice. In geometrically frustrated spin systems, interesting chiral correlations may develop that are related to the spin arrangement on triangular plaquettes. We report a study of the spin chirality on a two-dimensional geometrically frustrated lattice. Our new chemical synthesis methods allow us to produce large single crystal samples of KFe3(OH)6(SO4)2, an ideal Kagome lattice antiferromagnet. Combined thermodynamic and neutron scattering measurements reveal that the phase transition to the ordered ground-state is unusual. At low temperatures, application of a magnetic field induces a transition between states with different non-trivial spin-textures.Comment: 7 pages, 4 figure

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2(-/-) mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer