OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Regional Differences in Ethyicholine Mustard Aziridinium Ion (AF64A)-Induced Deficits in Presynaptic Cholinergic Markers for the Rat Central Nervous System1

ABSTRACT ABBREVIATiONS: SDAT, senile dementia of the Aizheimer's type; AF64A, ethyicholine mustard aziridinium ion; ChAT, choline acetyltransferase; SDHACU, sodium-dependent high-affinity choline uptake; PZ, pirenzepine; HC-3, hemicholinium-3; QNB, quinuclidinyl benzilate; CD, cis-methyldioxolane; acetyl CoA, acetyl Coenzyme; ANOVA, analysis of variance. 57

Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures

GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all of which most likely lead to loss of function of GAT-1 and thus reduced GABA re-uptake from the synapse. These individuals share many of the electrophysiological properties of Gat1-deficient mice, including spontaneous spike-wave discharges. Overall, pathogenic mutations occurred in 6/160 individuals with MAE, accounting for ∼4% of unsolved MAE cases

Initiation and Long-Term Instability of the East Antarctic Ice Sheet

Antarctica’s continental-scale ice sheets have evolved over the past 50 million years1,2,3,4. However, the dearth of ice-proximal geological records5,6,7,8 limits our understanding of past East Antarctic Ice Sheet (EAIS) behaviour and thus our ability to evaluate its response to ongoing environmental change. The EAIS is marine-terminating and grounded below sea level within the Aurora subglacial basin, indicating that this catchment, which drains ice to the Sabrina Coast, may be sensitive to climate perturbations9,10,11. Here we show, using marine geological and geophysical data from the continental shelf seaward of the Aurora subglacial basin, that marine-terminating glaciers existed at the Sabrina Coast by the early to middle Eocene epoch. This finding implies the existence of substantial ice volume in the Aurora subglacial basin before continental-scale ice sheets were established about 34 million years ago1,2,3,4. Subsequently, ice advanced across and retreated from the Sabrina Coast continental shelf at least 11 times during the Oligocene and Miocene epochs. Tunnel valleys12 associated with half of these glaciations indicate that a surface-meltwater-rich sub-polar glacial system existed under climate conditions similar to those anticipated with continued anthropogenic warming10,11. Cooling since the late Miocene13 resulted in an expanded polar EAIS and a limited glacial response to Pliocene warmth in the Aurora subglacial basin catchment14,15,16. Geological records from the Sabrina Coast shelf indicate that, in addition to ocean temperature, atmospheric temperature and surface-derived meltwater influenced East Antarctic ice mass balance under warmer-than-present climate conditions. Our results imply a dynamic EAIS response with continued anthropogenic warming and suggest that the EAIS contribution to future global sea-level projections10,11,15,17 may be under-estimated