The principal inhibitory neurotransmitter in the mammalian brain, ␥-aminobutyric acid (GABA), is thought to regulate memory processes by activating transient inhibitory postsynaptic currents. Here we describe a nonsynaptic, tonic form of inhibition in mouse CA1 pyramidal neurons that is generated by a distinct subpopulation of GABA type A receptors (GABA ARs). This tonic inhibitory conductance is predominantly mediated by ␣5 subunit-containing GABAARs (␣5GABAARs) that have different pharmacological and kinetic properties compared to postsynaptic receptors. GABAARs that mediate the tonic conductance are well suited to detect low, persistent, ambient concentrations of GABA in the extracellular space because they are highly sensitive to GABA and desensitize slowly. Moreover, the tonic current is highly sensitive to enhancement by amnestic drugs. Given the restricted expression of ␣5GABAARs to the hippocampus and the association between reduced ␣5GABAAR function and improved memory performance in behavioral studies, our results suggest that tonic inhibition mediated by ␣5GABAARs in hippocampal pyramidal neurons plays a key role in cognitive processes. The ␥-aminobutyric acid (GABA) subtype A receptor (GABA A R) is a pentameric anion-selective ion channel that assembles from different classes of subunits (␣1-6, ␤1-3, ␥1-3, ␦, , , and ) (1). The combination of various GABA A R subunits confers different biophysical and pharmacological properties and regulates regional and subcellular patterns of distribution (2, 3). The subunit composition critically determines agonist affinity, receptor kinetics, and sensitivity to a variety of clinically important drugs, including benzodiazepines and general anesthetics.Studies of gene-targeted mice have implicated specific GABA A R subunit isoforms in critical aspects of information processing in the brain. Notably, ␣5-null mutant mice (␣5Ϫ͞Ϫ) exhibit improved performance in the water maze model of spatial learning, a hippocampus-dependent learning task (4). Further, mice carrying a point mutation at position 105 of the ␣5 subunit (H105R) experience an unexpected selective reduction of ␣5GABA A Rs in hippocampal pyramidal neurons and improved performance for learning tasks (5). Pharmacological studies further support the involvement of ␣5GABA A Rs in learning processes; for example, ␣5 subunit-selective inverse agonists such as L-655,708 enhance learning performance in rats in the Morris water maze test (6, 7). Moreover, ␣5 subunitselective inverse agonists exhibit desirable nootropic effects without causing adverse convulsant activities associated with nonselective GABA A R inverse agonists. Thus, inhibition of ␣5GABA A Rs presents an attractive strategy for developing memory-enhancing drugs.The neuronal substrates underlying improved cognitive performance associated with reduced ␣5GABA A R function remain unknown. The ␣5 subunit has a unique and limited pattern of distribution in the mammalian brain. Although ␣5-containing receptors constitute Ͻ5% of the total GABA A R population...

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A fundamental objective of anesthesia research is to identify the receptors and brain regions that mediate the various behavioral components of the anesthetic state, including amnesia, immobility, and unconsciousness. Using complementary in vivo and in vitro approaches, we found that GABA A receptors that contain the ␣5 subunit (␣5GABA A Rs) play a critical role in amnesia caused by the prototypic intravenous anesthetic etomidate. Whole-cell recordings from hippocampal pyramidal neurons showed that etomidate markedly increased a tonic inhibitory conductance generated by ␣5GABA A Rs, whereas synaptic transmission was only slightly enhanced. Long-term potentiation (LTP) of field EPSPs recorded in CA1 stratum radiatum was reduced by etomidate in wild-type (WT) but not ␣5 null mutant (␣5Ϫ/Ϫ) mice. In addition, etomidate impaired memory performance of WT but not ␣5Ϫ/Ϫ mice for spatial and nonspatial hippocampal-dependent learning tasks. The brain concentration of etomidate associated with memory impairment in vivo was comparable with that which increased the tonic inhibitory conductance and blocked LTP in vitro. The ␣5Ϫ/Ϫ mice did not exhibit a generalized resistance to etomidate, in that the sedative-hypnotic effects measured with the rotarod, loss of righting reflex, and spontaneous motor activity were similar in WT and ␣5Ϫ/Ϫ mice. Deletion of the ␣5 subunit of the GABA A Rs reduced the amnestic but not the sedativehypnotic properties of etomidate. Thus, the amnestic and sedative-hypnotic properties of etomidate can be dissociated on the basis of GABA A R subtype pharmacology.

Among individuals without known CAD, nonobstructive and obstructive CAD by CCTA are associated with higher rates of mortality, with risk profiles differing for age and sex. Importantly, absence of CAD is associated with a very favorable prognosis.

Background Pericardial fat volume (PFV) and thoracic fat volume (TFV) can be routinely measured from noncontrast CT (NCT) performed for calculating coronary calcium score (CCS) and may predict major adverse cardiovascular event (MACE) risk. Methods From a registry of 2751 asymptomatic patients without known CAD and 4-year follow-up for MACE (cardiac death, myocardial infarction, stroke, late revascularization) after NCT, we compared 58 patients with MACE (“EVENTS”) to 174 same-sex event-free controls matched by a propensity score to account for age, risk factors, and CCS. TFV was automatically calculated, and PFV was calculated with manual assistance in defining the pericardial contour, within which fat voxels were automatically identified. Independent relationships of PFV and TFV to MACE were evaluated using conditional multivariable logistic regression. Results EVENTS had higher mean PFV (101.8±49.2 cm3 vs. 84.9±37.7 cm3, p=0.007) and TFV (204.7±90.3 cm3 vs. 177±80.3 cm3, p=0.029) and higher frequencies of PFV>125 cm3 (33% vs. 14%, p=0.002) and TFV>250 cm3 (31% vs. 17%, p=0.025). After adjusting for Framingham Risk Score, CCS, and body-mass-index, PFV and TFV were significantly associated with MACE (odds ratio (OR) 1.74, 95%CI 1.03–2.95 for each doubling of PFV; OR 1.78, 95%CI 1.01–3.14 for TFV). Areas-under-the-curve from receiver operating characteristic analyses showed a trend of improved MACE prediction when PFV was added to FRS and CCS (0.73 vs 0.68, p=0.058). Addition of PFV, but not TFV, to FRS and CCS improved estimated specificity (0.72 vs 0.66, p=0.008) and overall accuracy (0.70 vs 0.65, p=0.009) in predicting MACE. Conclusion Asymptomatic patients who experience MACE exhibit greater PFV on pre-MACE NCT when compared to event-free controls with similar cardiovascular risk profiles. Our preliminary findings suggest that PFV may help improve prediction of MACE.

Background Guidelines for the management of patients with suspected coronary artery disease (CAD) rely on the age, sex, and angina typicality-based pre-test probabilities of angiographically significant CAD derived from invasive coronary angiography (“Guideline Probabilities”). Reliability of Guideline Probabilities has not been investigated in patients referred to noninvasive CAD testing. Methods and Results We identified 14048 consecutive patients with suspected CAD who underwent coronary computed tomographic angiography (CTA) Angina typicality was recorded using accepted criteria. Pre-test likelihoods of CAD with ≥50% diameter stenosis (CAD50) and ≥70% diameter stenosis (CAD70) were calculated using Guideline Probabilities. CTA images were evaluated by ≥1 expert reader to determine presence of CAD50 and CAD70. Typical angina was associated with the highest prevalence of CAD50 (40% in men, 19% in women) and CAD70 (27% men, 11% women) when compared to other symptom categories (p<0.001 for all). Observed CAD50 and CAD70 prevalence were substantially lower than that predicted by Guideline Probabilities in the overall population (18% vs. 51% for CAD50, 10% vs. 42% for CAD70, p<0.001), driven by pronounced differences in patients with atypical angina (15% vs. 47% for CAD50, 7% vs. 37% for CAD70) and typical angina (29% vs. 86% for CAD50, 19% vs. 71% for CAD70). Marked overestimation of disease prevalence by Guideline Probabilities was found at all participating centers and across all sex and age subgroups. Conclusion In this multinational study of patients referred for coronary CTA, determination of pre-test likelihood of angiographically significant CAD by the invasive angiography-based Guideline Probabilities greatly overestimates the actual prevalence of disease.

In symptomatic patients with a CAC score of 0, obstructive CAD is possible and is associated with increased cardiovascular events. CAC scoring did not add incremental prognostic information to CCTA.

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