Presynaptic GABAB receptors functionally uncouple somatostatin interneurons from the active hippocampal network.

Information processing in cortical neuronal networks relies on properly balanced excitatory and inhibitory neurotransmission. A ubiquitous motif for maintaining this balance is the somatostatin interneuron (SOM-IN) feedback microcircuit. Here, we investigated the modulation of this microcircuit by presynaptic GABAB receptors (GABABRs) in the rodent hippocampus. Whole-cell recordings from SOM-INs revealed that both excitatory and inhibitory synaptic inputs are strongly inhibited by GABABRs, while optogenetic activation of the interneurons shows that their inhibitory output is also strongly suppressed. Electron microscopic analysis of immunogold-labelled freeze-fracture replicas confirms that GABABRs are highly expressed presynaptically at both input and output synapses of SOM-INs. Activation of GABABRs selectively suppresses the recruitment of SOM-INs during gamma oscillations induced in vitro. Thus, axonal GABABRs are positioned to efficiently control the input and output synapses of SOM-INs and can functionally uncouple them from local network with implications for rhythmogenesis and the balance of entorhinal versus intrahippocampal afferents.

Renal Cell Carcinoma in the Head and Neck: Case Presentation of a Patient With a Rare Metastatic Pattern.

Renal cell carcinoma is known for its metastatic potential, however, metastasis to the head and neck are rare. We present a 71-year-old man who presented with a palpable tongue mass. The positron-emission tomographic-computed tomographic scan revealed enhancements in the left tongue base, left thyroid, left shoulder musculature, right upper thigh, and right paratracheal mediastinal lymph nodes. Subsequent tongue and trapezius muscle biopsies had immunochemical stains consistent with renal cell carcinoma metastasis. This article discusses an uncommon metastatic pattern of renal cell carcinoma to the tongue and what is the second reported metastasis of renal cell carcinoma to the trapezius muscle.

An ER Assembly Line of AMPA-Receptors Controls Excitatory Neurotransmission and Its Plasticity.

Excitatory neurotransmission and its activity-dependent plasticity are largely determined by AMPA-receptors (AMPARs), ion channel complexes whose cell physiology is encoded by their interactome. Here, we delineate the assembly of AMPARs in the endoplasmic reticulum (ER) of native neurons as multi-state production line controlled by distinct interactome constituents: ABHD6 together with porcupine stabilizes pore-forming GluA monomers, and the intellectual-disability-related FRRS1l-CPT1c complexes promote GluA oligomerization and co-assembly of GluA tetramers with cornichon and transmembrane AMPA-regulatory proteins (TARP) to render receptor channels ready for ER exit. Disruption of the assembly line by FRRS1l deletion largely reduces AMPARs in the plasma membrane, impairs synapse formation, and abolishes activity-dependent synaptic plasticity, while FRRS1l overexpression has the opposite effect. As a consequence, FRSS1l knockout mice display severe deficits in learning tasks and behavior. Our results provide mechanistic insight into the stepwise biogenesis of AMPARs in native ER membranes and establish FRRS1l as a powerful regulator of synaptic signaling and plasticity.

Munc13-3 Is Required for the Developmental Localization of Ca2+ Channels to Active Zones and the Nanopositioning of Cav2.1 Near Release Sensors.

Spatial relationships between Cav channels and release sensors at active zones (AZs) are a major determinant of synaptic fidelity. They are regulated developmentally, but the underlying molecular mechanisms are largely unclear. Here, we show that Munc13-3 regulates the density of Cav2.1 and Cav2.2 channels, alters the localization of Cav2.1, and is required for the development of tight, nanodomain coupling at parallel-fiber AZs. We combined EGTA application and Ca2+-channel pharmacology in electrophysiological and two-photon Ca2+ imaging experiments with quantitative freeze-fracture immunoelectron microscopy and mathematical modeling. We found that a normally occurring developmental shift from release being dominated by Ca2+ influx through Cav2.1 and Cav2.2 channels with domain overlap and loose coupling (microdomains) to a nanodomain Cav2.1 to sensor coupling is impaired in Munc13-3-deficient synapses. Thus, at AZs lacking Munc13-3, release remained triggered by Cav2.1 and Cav2.2 microdomains, suggesting a critical role of Munc13-3 in the formation of release sites with calcium channel nanodomains.

Tyrosine kinase 2 is not limiting human antiviral type III interferon responses.

Tyrosine kinase 2 (TYK2) associates with interferon (IFN) alpha receptor, IL-10 receptor (IL-10R) beta and other cytokine receptor subunits for signal transduction, in response to various cytokines, including type-I and type-III IFNs, IL-6, IL-10, IL-12 and IL-23. Data on TYK2 dependence on cytokine responses and in vivo consequences of TYK2 deficiency are inconsistent. We investigated a TYK2 deficient patient, presenting with eczema, skin abscesses, respiratory infections and IgE levels >1000 U/mL, without viral or mycobacterial infections and a corresponding cellular model to analyze the role of TYK2 in type-III IFN mediated responses and NK-cell function. We established a novel simple diagnostic monocyte assay to show that the mutation completely abolishes the IFN-α mediated antiviral response. It also partly reduces IL-10 but not IL-6 mediated signaling associated with reduced IL-10Rß expression. However, we found almost normal type-III IFN signaling associated with minimal impairment of virus control in a TYK2 deficient human cell line. Contrary to observations in TYK2 deficient mice, NK-cell phenotype and function, including IL-12/IL-18 mediated responses, were normal in the patient. Thus, preserved type-III IFN responses and normal NK-cell function may contribute to antiviral protection in TYK2 deficiency leading to a surprisingly mild human phenotype.

Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome.

Genetic disorders affecting biogenesis and transport of lysosome-related organelles are heterogeneous diseases frequently associated with albinism. We studied a patient with albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generalized seizures, and impaired hearing but with no mutation in genes so far associated with albinism and immunodeficiency. Whole exome sequencing identified a homozygous mutation in AP3D1 that leads to destabilization of the adaptor protein 3 (AP3) complex. AP3 complex formation and the degranulation defect in patient T cells were restored by retroviral reconstitution. A previously described hypopigmented mouse mutant with an Ap3d1 null mutation (mocha strain) shares the neurologic phenotype with our patient and shows a platelet storage pool deficiency characteristic of Hermansky-Pudlak syndrome (HPS) that was not studied in our patient because of a lack of bleeding. HPS2 caused by mutations in AP3B1A leads to a highly overlapping phenotype without the neurologic symptoms. The AP3 complex exists in a ubiquitous and a neuronal form. AP3D1 codes for the AP3δ subunit of the complex, which is essential for both forms. In contrast, the AP3ß3A subunit, affected in HPS2 patients, is substituted by AP3ß3B in the neuron-specific heterotetramer. AP3δ deficiency thus causes a severe neurologic disorder with immunodeficiency and albinism that we propose to classify as HPS10.

Comparison of Food Intake Among Infants and Toddlers Participating in a South Central Texas WIC Program Reveals Some Improvements After WIC Package Changes.

In 2009, WIC began issuing revised food packages with the intent of improving dietary practices such as breastfeeding, delaying the introduction of complementary foods until about 6 months, limiting juice intake, and increasing intake of fruits, vegetables, whole grains, and baby food meats as appropriate for age. This observational study investigated whether dietary intake and feeding practices of a sample of majority-Hispanic infants and toddlers participating in a WIC clinic in south central Texas improved after the package changes. Feeding practices data and 24-h recalls were collected during telephone interviews with 84 caregivers of infants (4-12 months) and toddlers (1-2 years) in 2009 before the package change and with 112 caregivers in 2011 after the package change. The Nutrition Data System for Research was used to collect 24-h recalls. Outcomes for the two study years were compared using Chi square analysis for categorical and Mann-Whitney U analysis for continuous variables. Breastfeeding initiation, breastfeeding duration, age of introduction of complementary foods, and exposures to baby food fruits, vegetables, and meats among infants did not improve after the package changes. Significantly fewer infants received cereal in their bottles and fewer toddlers consumed vegetables and eggs after the package changes. The observed feeding practices of infants and toddlers among this sample did not reflect the WIC package changes. Strategic and comprehensive breastfeeding and nutrition education are recommended. Package modifications such as adding eggs back to the toddler package and allowing more flexibility for purchasing fresh produce and baby foods may be warranted.

Differences in energy and micronutrient intakes among Central Texas WIC infants and toddlers after the package change.

OBJECTIVE: To assess nutrient intakes after the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) package changes within an at-risk, majority Hispanic population of WIC infants and toddlers in Central Texas. METHODS: For this cross-sectional observational study, Nutrition Data System for Research was used to collect 24-hour recalls of infants and toddlers from a sample of caregivers in 2009 and 2011. Usual nutrient intakes were estimated and compared with Dietary Reference Intakes using the National Cancer Institute method. Mean single-day nutrient intakes were compared using Mann-Whitney tests. RESULTS: Subjects were children ages 4-24 months (2009, n = 84; 2011, n = 120). After the package change, usual energy intakes exceeded recommended levels for infants (79% in excess of Estimated Energy Requirement), but fell below recommended levels for toddlers (88% below Estimated Energy Requirement). Also after the package change, mean usual intake of vitamin D was below the Estimated Average Requirement for toddlers (6.54 vs 10 µg), and mean usual intakes of vitamin A and zinc exceeded the Tolerable Upper Intake Level for all groups. CONCLUSIONS AND IMPLICATIONS: Whereas lower energy intake may reduce obesity risk, in toddlers, lower energy intake increases risk for micronutrient deficiencies. Recommendations include culturally appropriate education and reinstatement of previous milk allotment in the toddler package.