Tonic GABAa current in absence epilepsy

Typical absence seizures are characteristic of many idiopathic generalised epilepsies and the only seizure-type in childhood absence epilepsy. We know that absence seizures arise in thalamocortical networks and that GABAergic agents exacerbate or induce absences. Furthermore, raised levels of GABA have been identified in the ventrobasal thalamus in an established genetic animal model (genetic absence epilepsy rats from Strasbourg GAERS), which was later suggested as a result of aberrant GABA uptake. I have shown that enhanced tonic GABAa current in TC neurons of the VB is a common phenomenon across genetic and pharmacological models of absence seizures. Furthermore, my data show that increased extrasynaptic GABAaR (cGABAaR) function in the VB is both sufficient and necessary to induce SWDs. This is supported by the fact that focal intrathalamic application of a selective agonist for eGABAARs, THIP, was sufficient to elicit SWDs in normal animals and that mice lacking cGABAaRs were resistant to absence seizure induction by y-butyrolactone. Moreover, I have presented data that directly implicate aberrant type-1 GABA transporters (GAT-1) in SWD generation in vivo, with GAT-1 knockout mice exhibiting spontaneous SWDs and focal thalamic administration of the GAT-1 blocker, N0711, inducing SWDs in normal rats a potential new model of absence epilepsy. In addition, my data indicate that activation of postsynaptic GABAbRs enhances tonic GABAA current, presumably via the Gl o protein coupled adenyl cyclase pathway, which was present under control conditions and occurred in several brain areas. This postsynaptic GABAb-cGABAaR link is further supported by the fact that GBL failed to induce SWDs in 5-subunit knockout mice. Thus, one of the cellular thalamic pathologies that characterises absence seizures is an astrocyte-specific aberrant GAT-1 with the resulting elevated extracellular GABA level enhancing tonic GABAa current through two mechanisms: direct activation of high affinity eGABAARs and indirect increase in eGABAAR function due to activation of postsynaptic GABAbRs.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Tonic GABAa current in absence epilepsy

Typical absence seizures are characteristic of many idiopathic generalised epilepsies and the only seizure-type in childhood absence epilepsy. We know that absence seizures arise in thalamocortical networks and that GABAergic agents exacerbate or induce absences. Furthermore, raised levels of GABA have been identified in the ventrobasal thalamus in an established genetic animal model (genetic absence epilepsy rats from Strasbourg GAERS), which was later suggested as a result of aberrant GABA uptake. I have shown that enhanced tonic GABAa current in TC neurons of the VB is a common phenomenon across genetic and pharmacological models of absence seizures. Furthermore, my data show that increased extrasynaptic GABAaR (cGABAaR) function in the VB is both sufficient and necessary to induce SWDs. This is supported by the fact that focal intrathalamic application of a selective agonist for eGABAARs, THIP, was sufficient to elicit SWDs in normal animals and that mice lacking cGABAaRs were resistant to absence seizure induction by y-butyrolactone. Moreover, I have presented data that directly implicate aberrant type-1 GABA transporters (GAT-1) in SWD generation in vivo, with GAT-1 knockout mice exhibiting spontaneous SWDs and focal thalamic administration of the GAT-1 blocker, N0711, inducing SWDs in normal rats a potential new model of absence epilepsy. In addition, my data indicate that activation of postsynaptic GABAbRs enhances tonic GABAA current, presumably via the Gl o protein coupled adenyl cyclase pathway, which was present under control conditions and occurred in several brain areas. This postsynaptic GABAb-cGABAaR link is further supported by the fact that GBL failed to induce SWDs in 5-subunit knockout mice. Thus, one of the cellular thalamic pathologies that characterises absence seizures is an astrocyte-specific aberrant GAT-1 with the resulting elevated extracellular GABA level enhancing tonic GABAa current through two mechanisms: direct activation of high affinity eGABAARs and indirect increase in eGABAAR function due to activation of postsynaptic GABAbRs.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

GABAB receptors regulate extrasynaptic GABAA receptors

Tonic inhibitory GABAA receptor-mediated currents are observed in numerous cell types in the CNS, including thalamocortical neurons of the ventrobasal thalamus, dentate gyrus granule cells, and cerebellar granule cells. Here we show that in rat brain slices, activation of postsynaptic GABAB receptors enhances the magnitude of the tonic GABAA current recorded in these cell types via a pathway involving Gi/o G proteins, adenylate cyclase, and cAMP-dependent protein kinase. Using a combination of pharmacology and knockout mice, we show that this pathway is independent of potassium channels or GABA transporters. Furthermore, the enhancement in tonic current is sufficient to significantly alter the excitability of thalamocortical neurons. These results demonstrate for the first time a postsynaptic crosstalk between GABAB and GABAA receptors.peer-reviewe

Optoactivation of locus ceruleus neurons evokes bidirectional changes in thermal nociception in rats

International audiencePontospinal noradrenergic neurons are thought to form part of a descending endogenous analgesic system that exerts inhibitory influences on spinal nociception. Using optogenetic targeting, we tested the hypothesis that excitation of the locus ceruleus (LC) is antinociceptive. We transduced rat LC neurons by direct injection of a lentiviral vector expressing channelrhodopsin2 under the control of the PRS promoter. Subsequent optoactivation of the LC evoked repeatable, robust, antinociceptive (-4.7 degrees C +/- 1.0, p < 0.0001) or pronociceptive (-4.4 degrees C +/- 0.7, p < 0.0001) changes in hindpaw thermal withdrawal thresholds. Post hoc anatomical characterization of the distribution of transduced somata referenced against the position of the optical fiber and subsequent further functional analysis showed that antinociceptive actions were evoked from a distinct, ventral subpopulation of LC neurons. Therefore, the LC is capable of exerting potent, discrete, bidirectional influences on thermal nociception that are produced by specific subpopulations of noradrenergic neurons. This reflects an underlying functional heterogeneity of the influence of the LC on the processing of nociceptive information

Enhanced tonic GABAA inhibition in typical absence epilepsy

The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired GABAergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent ‘tonic’ inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT–1 in the genetic models tested, and GAT–1 is critical in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioural correlates of seizures in normal animals. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic significance, and highlight novel therapeutic targets for the treatment of absence epilepsy.peer-reviewe

The seeds of divergence: the economy of French North America, 1688 to 1760

Generally, Canada has been ignored in the literature on the colonial origins of divergence with most of the attention going to the United States. Late nineteenth century estimates of income per capita show that Canada was relatively poorer than the United States and that within Canada, the French and Catholic population of Quebec was considerably poorer. Was this gap long standing? Some evidence has been advanced for earlier periods, but it is quite limited and not well-suited for comparison with other societies. This thesis aims to contribute both to Canadian economic history and to comparative work on inequality across nations during the early modern period. With the use of novel prices and wages from Quebec—which was then the largest settlement in Canada and under French rule—a price index, a series of real wages and a measurement of Gross Domestic Product (GDP) are constructed. They are used to shed light both on the course of economic development until the French were defeated by the British in 1760 and on standards of living in that colony relative to the mother country, France, as well as the American colonies. The work is divided into three components. The first component relates to the construction of a price index. The absence of such an index has been a thorn in the side of Canadian historians as it has limited the ability of historians to obtain real values of wages, output and living standards. This index shows that prices did not follow any trend and remained at a stable level. However, there were episodes of wide swings—mostly due to wars and the monetary experiment of playing card money. The creation of this index lays the foundation of the next component. The second component constructs a standardized real wage series in the form of welfare ratios (a consumption basket divided by nominal wage rate multiplied by length of work year) to compare Canada with France, England and Colonial America. Two measures are derived. The first relies on a “bare bones” definition of consumption with a large share of land-intensive goods. This measure indicates that Canada was poorer than England and Colonial America and not appreciably richer than France. However, this measure overestimates the relative position of Canada to the Old World because of the strong presence of land-intensive goods. A second measure is created using a “respectable” definition of consumption in which the basket includes a larger share of manufactured goods and capital-intensive goods. This second basket better reflects differences in living standards since the abundance of land in Canada (and Colonial America) made it easy to achieve bare subsistence, but the scarcity of capital and skilled labor made the consumption of luxuries and manufactured goods (clothing, lighting, imported goods) highly expensive. With this measure, the advantage of New France over France evaporates and turns slightly negative. In comparison with Britain and Colonial America, the gap widens appreciably. This element is the most important for future research. By showing a reversal because of a shift to a different type of basket, it shows that Old World and New World comparisons are very sensitive to how we measure the cost of living. Furthermore, there are no sustained improvements in living standards over the period regardless of the measure used. Gaps in living standards observed later in the nineteenth century existed as far back as the seventeenth century. In a wider American perspective that includes the Spanish colonies, Canada fares better. The third component computes a new series for Gross Domestic Product (GDP). This is to avoid problems associated with using real wages in the form of welfare ratios which assume a constant labor supply. This assumption is hard to defend in the case of Colonial Canada as there were many signs of increasing industriousness during the eighteenth and nineteenth centuries. The GDP series suggest no long-run trend in living standards (from 1688 to circa 1765). The long peace era of 1713 to 1740 was marked by modest economic growth which offset a steady decline that had started in 1688, but by 1760 (as a result of constant warfare) living standards had sunk below their 1688 levels. These developments are accompanied by observations that suggest that other indicators of living standard declined. The flat-lining of incomes is accompanied by substantial increases in the amount of time worked, rising mortality and rising infant mortality. In addition, comparisons of incomes with the American colonies confirm the results obtained with wages— Canada was considerably poorer. At the end, a long conclusion is provides an exploratory discussion of why Canada would have diverged early on. In structural terms, it is argued that the French colony was plagued by the problem of a small population which prohibited the existence of scale effects. In combination with the fact that it was dispersed throughout the territory, the small population of New France limited the scope for specialization and economies of scale. However, this problem was in part created, and in part aggravated, by institutional factors like seigneurial tenure. The colonial origins of French America’s divergence from the rest of North America are thus partly institutional

Thalamic extrasynaptic GABAA receptors are required for typical absence seizures

Aberrant GABAergic inhibition in thalamo-cortical networks has been identified as a potential mechanism for spike-and-wave discharge (SWD) generation. Thalamocortical (TC) neurons in the ventrobasal (VB) thalamus receive both ‘phasic’ and ‘tonic’ GABAA receptor mediated inhibition, generated by synaptic and extrasynaptic delta-subunit containing receptors, respectively [Cope et al., 2005; J. Neurosci. 25: 11553]. We have shown a selective increase of tonic GABAA receptor-mediated inhibition in pharmacological as well as in polygenic and monogenic rat and mouse models of absence epilepsy due to an impairment of GABA transporter-1 (GAT-1) activity [Society for Neuroscience 2007, 142.7, 142.8, 142.9]. Therefore, we suggested that extrasynaptic GABAA receptor gain-of-function in VB TC neurons is a necessary requirement for the appearance of SWDs. To directly test this hypothesis, we have now pharmacologically and genetically targeted extrasynaptic GABAA receptors in VB and monitored EEG and behavioural correlates of absence epilepsy in normal Wistar rats, Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and GABAA receptor delta-subunit knockout mice. All experiments were conducted in accordance with the UK Animal Scientific Procedure Act. Reverse microdialysis of the selective extrasynaptic GABAA agonist THIP (70 and 100 μM, both n=5) and the selective GAT-1 inhibitor NO-711 (200 μM, n=5) into the VB induced SWDs and behavioural correlates of absence seizures in normal Wistar rats. THIP- and NO-711-induced SWDs were suppressed by systemic administration of the anti-absence drug ethosuximide (ETX, 100 mg/kg, n=5). In addition, we “knocked-down” extrasynaptic GABAA receptors in TC cells of GAERS by directly infusing a δ subunit specific antisense oligodeoxynucleotide (ODN, 1 and 2 nMol/μl, n=5 and 6, respectively) into the VB. The antisense ODN produced a marked reduction (~70% at 2 nMol) of the total time spent in seizures and the number of SWDs, whilst infusion of a missense ODN (1-2 nMol/μl, n=5) was ineffective. Lastly, systemic administration of 50 mg/kg of gamma-butyrolactone induced absence seizures in wild type mice, which were significantly reduced in the delta-subunit knockout mice (84% decrease in the total time spent in seizures and 53% reduction in number of SWDs). Our data demonstrate that extrasynaptic GABAA receptor gain-of-function in VB TC neurons is a necessary and sufficient requirement for the appearance of a pure absence epilepsy phenotype, and that GAT-1 critically controls SWD genesis.peer-reviewe

‘The Silence is roaring’: sterilization, reproductive rights and women with intellectual disabilities

This paper reviews the history of sterilization of women with intellectual disabilities, and considers its relevance to current practice regarding reproductive choice and futures. The paper provides an overview of published research on historical practices, focusing on the UK, the US, Canada and the Nordic countries. Most of this research draws upon written records, centering on eugenics debates. However, emerging oral history testimonies gathered by the authors suggest that sterilization procedures were also conducted in the community, the result of private negotiations between parents and medical practitioners. The article presents these accounts and calls for an end to a ‘roaring silence’ on this issue. More empirical studies are needed to recover the experiences of women who have been sterilized and to explore how decisions about reproductive choice and capacity were made in the past and continue to be made today. Key words: Sterilization; intellectual disability; contraception; history