Hyperexcitability of the local cortical circuit in mouse models of tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a neurogenetic disorder associated with epilepsy, intellectual disabilities, and autistic behaviors. These neurological symptoms result from synaptic dysregulations, which shift a balance between excitation and inhibition. To decipher the synaptic substrate of hyperexcitability, we examined pan-neuronal Tsc1 knockout mouse and found a reduction in surface expression of a GABA receptor (GABAR) subunit but not AMPA receptor (AMPAR) subunit. Using electrophysiological recordings, we found a significant reduction in the frequency of GABAR-mediated miniature inhibitory postsynaptic currents (GABAR-mIPSCs) but not AMPAR-mediated miniature excitatory postsynaptic currents (AMPAR-mEPSCs) in layer 2/3 pyramidal neurons. To determine a subpopulation of interneurons that are especially vulnerable to the absence of TSC1 function, we also analyzed two strains of conditional knockout mice targeting two of the prominent interneuron subtypes that express parvalbumin (PV) or somatostatin (SST). Unlike pan-neuronal knockout mice, both interneuron-specific Tsc-1 knockout mice did not develop spontaneous seizures and grew into adults. Further, the properties of AMPAR-mEPSCs and GABAR-mIPSCs were normal in both Pv-Cre and Sst-Cre x Tsc1fl/fl knockout mice. These results indicate that removal of TSC1 from all neurons in a local cortical circuit results in hyperexcitability while connections between pyramidal neurons and interneurons expressing PV and SST are preserved in the layer 2/3 visual cortex. Our study suggests that another inhibitory cell type or a combination of multiple subtypes may be accountable for hyperexcitability in TSC. Keywords: Tuberous sclerosis complex; E/I balance; AMPA receptor; GABA receptor; Autism; Epilepsy; mTOR pathwa

Gut microbiota functions: metabolism of nutrients and other food components

The diverse microbial community that inhabits the human gut has an extensive metabolic repertoire that is distinct from, but complements the activity of mammalian enzymes in the liver and gut mucosa and includes functions essential for host digestion. As such, the gut microbiota is a key factor in shaping the biochemical profile of the diet and, therefore, its impact on host health and disease. The important role that the gut microbiota appears to play in human metabolism and health has stimulated research into the identification of specific microorganisms involved in different processes, and the elucidation of metabolic pathways, particularly those associated with metabolism of dietary components and some host-generated substances. In the first part of the review, we discuss the main gut microorganisms, particularly bacteria, and microbial pathways associated with the metabolism of dietary carbohydrates (to short chain fatty acids and gases), proteins, plant polyphenols, bile acids, and vitamins. The second part of the review focuses on the methodologies, existing and novel, that can be employed to explore gut microbial pathways of metabolism. These include mathematical models, omics techniques, isolated microbes, and enzyme assays

Apparent underreporting of cigarette consumption among Mexican American smokers.

To determine the accuracy of self-report of cigarette consumption among Mexican American smokers, we compared self-reported cigarette use and serum cotinine concentrations in a sample of 547 participants in the Hispanic Health and Nutrition Examination Survey (HHANES). We defined underreporting of cigarette use as a cotinine to cigarette-per-day ratio of greater than 0.142 microM/l which represented a substantial discrepancy between self-reported consumption and serum cotinine. Of the 98 men and 97 women who reported smoking one to nine cigarettes/day, 20.4 percent and 24.7 percent, respectively, underreported their cigarette consumption. Underreporting was less common among men and women smoking 10 to 19 cigarettes/day (8.3 percent and 10.8 percent, respectively) and 20 or more cigarettes/day (2.2 percent and 2.9 percent, respectively). Comparison of underreporters to other smokers by demographic characteristics within sex and cigarettes/day categories showed no differences. Differences in cotinine metabolism and extremely efficient smoking are alternative explanations that can not be ruled out with these data. We believe, however, that a proportion of Mexican American light smokers may underreport the quantity of cigarettes smoked per day, and may truly be moderate or heavy smokers

Ethnic Comparison of Attitudes and Beliefs About Cigarette Smoking

OBJECTIVE: To determine if hypothesized differences in attitudes and beliefs about cigarette smoking between Latino and non-Latino white smokers are independent of years of formal education and number of cigarettes smoked per day. DESIGN: Cross-sectional survey using a random digit dial telephone method. SETTING: San Francisco census tracts with at least 10% Latinos in the 1990 Census. PARTICIPANTS: Three hundred twelve Latinos (198 men and 114 women) and 354 non-Latino whites (186 men and 168 women), 18 to 65 years of age, who were current cigarette smokers participated. MEASUREMENTS AND MAIN RESULTS: Self-reports of cigarette smoking behavior, antecedents to smoking, reasons to quit smoking, and reasons to continue smoking were the measures. Latino smokers were younger (36.6 vs 39.6 years, p < .01), had fewer years of education (11.0 vs 14.3 years, p < .001), and smoked on average fewer cigarettes per day (9.7 vs 20.1, p < .001). Compared with whites, Latino smokers were less likely to report smoking “almost always or often” after 13 of 17 antecedents (each p < .001), and more likely to consider it important to quit for 12 of 15 reasons (each p < .001). In multivariate analyses after adjusting for gender, age, education, income, and number of cigarettes smoked per day, Latino ethnicity was a significant predictor of being less likely to smoke while talking on the telephone (odds ratio [OR] 0.41; 95% confidence interval [CI] 0.26, 0.64), drinking alcoholic beverages (OR 0.66; 95% CI 0.44, 0.99), after eating (OR 0.55, 95% CI 0.37, 0.81), or at a bar (OR 0.62, 95% CI 0.41, 0.94), and a significant predictor of being more likely to smoke at a party (OR 1.72; 95% CI 1.14, 2.60). Latino ethnicity was a significant predictor of considering quitting important because of being criticized by family (OR 1.93; 95% CI 1.26, 2.98), burning clothes (OR 1.57; 95% CI 1.02, 2.42), damaging children's health (OR 1.67; 95% CI 1.08, 2.57), bad breath (OR 2.07; 95% CI 1.40, 3.06), family pressure (OR 1.67; 95% CI 1.10, 2.60), and being a good example to children (OR 1.83; 95% CI 1.21, 2.76). CONCLUSIONS: Differences in attitudes and beliefs about cigarette smoking between Latinos and whites are independent of education and number of cigarettes smoked. We recommend that these ethnic differences be incorporated into smoking cessation interventions for Latino smokers