Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate

Kv7.2 and Kv7.3 subunits underlie the M-current, a neuronal K(+) current characterized by an absolute functional requirement for phosphatidylinositol 4,5-bisphosphate (PIP(2)). Kv7.2 gene mutations cause early-onset neonatal seizures with heterogeneous clinical outcomes, ranging from self-limiting benign familial neonatal seizures to severe early-onset epileptic encephalopathy (Kv7.2-EE). In this study, the biochemical and functional consequences prompted by a recurrent variant (R325G) found independently in four individuals with severe forms of neonatal-onset EE have been investigated. Upon heterologous expression, homomeric Kv7.2 R325G channels were non-functional, despite biotin-capture in Western blots revealed normal plasma membrane subunit expression. Mutant subunits exerted dominant-negative effects when incorporated into heteromeric channels with Kv7.2 and/or Kv7.3 subunits. Increasing cellular PIP(2) levels by co-expression of type 1γ PI(4)P5-kinase (PIP5K) partially recovered homomeric Kv7.2 R325G channel function. Currents carried by heteromeric channels incorporating Kv7.2 R325G subunits were more readily inhibited than wild-type channels upon activation of a voltage-sensitive phosphatase (VSP), and recovered more slowly upon VSP switch-off. These results reveal for the first time that a mutation-induced decrease in current sensitivity to PIP(2) is the primary molecular defect responsible for Kv7.2-EE in individuals carrying the R325G variant, further expanding the range of pathogenetic mechanisms exploitable for personalized treatment of Kv7.2-related epilepsies

Polinômios para modelar a trajetória de crescimento de tourinhos em provas de ganho em peso.

Este trabalho foi realizado com o objetivo de identificar o tipo de polinômio e a ordem de ajuste mais adequados para modelagem da trajetória média de crescimento de tourinhos Nelore, MA (21/32 Charolês + 11/32 Nelore) e Canchim em provas de ganho em peso. As trajetórias médias de crescimento foram ajustadas por meio de polinômios ordinários e de Legendre (linear até quíntico) e Bsplines quadráticos (com dois até seis intervalos regulares). Nas comparações envolvendo apenas os modelos com os mesmos números de parâmetros, os B-splines promoveram os melhores ajustes. O modelo com polinômio B-spline com seis intervalos foi considerado como o melhor para as raças Canchim e MA. Para a raça Nelore, o B-spline com quatro intervalos foi o modelo com melhor ajuste de acordo com o Critério de Informação de Akaike Consistente

Recent Findings on AMPA Receptor Recycling

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) are tetrameric protein complexes that mediate most of the fast-excitatory transmission in response to the neurotransmitter glutamate in neurons. The abundance of AMPA-Rs at the surface of excitatory synapses establishes the strength of the response to glutamate. It is thus evident that neurons need to tightly regulate this feature, particularly in the context of all synaptic plasticity events, which are considered the biological correlates of higher cognitive functions such as learning and memory. AMPA-R levels at the synapse are regulated by insertion of newly synthesized receptors, lateral diffusion on the plasma membrane and endosomal cycling. The latter is likely the most important especially for synaptic plasticity. This process starts with the endocytosis of the receptor from the cell surface and is followed by either degradation, if the receptor is directed to the lysosomal compartment, or reinsertion at the cell surface through a specialized endosomal compartment called recycling endosomes. Although the basic steps of this process have been discovered, the details and participation of additional regulatory proteins are still being discovered. In this review article, we describe the most recent findings shedding light on this crucial mechanism of synaptic regulation

TARP γ-7 selectively enhances synaptic expression of calcium-permeable AMPARs

Regulation of calcium-permeable AMPA receptors (CP-AMPARs) is crucial in normal synaptic function and neurological disease states. Although transmembrane AMPAR regulatory proteins (TARPs) such as stargazin (γ-2) modulate the properties of calcium-impermeable AMPARs (CI-AMPARs) and promote their synaptic targeting, the TARP-specific rules governing CP-AMPAR synaptic trafficking remain unclear. We used RNA interference to manipulate AMPAR-subunit and TARP expression in γ-2–lacking stargazer cerebellar granule cells—the classic model of TARP deficiency. We found that TARP γ-7 selectively enhanced the synaptic expression of CP-AMPARs and suppressed CI-AMPARs, identifying a pivotal role of γ-7 in regulating the prevalence of CP-AMPARs. In the absence of associated TARPs, both CP-AMPARs and CI-AMPARs were able to localize to synapses and mediate transmission, although their properties were altered. Our results also establish that TARPed synaptic receptors in granule cells require both γ-2 and γ-7 and reveal an unexpected basis for the loss of AMPAR-mediated transmission in stargazer mice

Evaluation of nutritional status among school-aged children in rural Kwahu-eastern region, Ghana; anthropometric measures and environmental influences

School-age children in developing countries are particularly vulnerable to undernutrition as the priority of nutritional interventions focus on fetal development and the first years of life. This study examines anthropometric indices of school-age children in five communities located in rural Kwahu-Eastern Region, Ghana, West Africa and discusses environmental influences that contribute to their nutritional and growth status. Anthropometric indices of heights and weights were obtained from 411 school- aged children, (5-12 years old) in 5 villages (Asakraka, Awiseasu, Miaso, Oframase and Oworobong) during June 2012. Anthropometric parameters and influences that contributed to nutritional status (environmental, health facilities, availability of markets and gender) were assessed. Factorial ANOVAs were conducted with age, gender and village as factors for the z-score for ‘BMI-for-age’ and the z-score for ‘height-for-age’. The z-score of ‘BMI-for-age’ showed a significant two-way interaction effect between ‘Age’ and ‘Village’, F (4, 391) = 6.06, p-value < 0.001, η2 = 0.06. The mean z-score for ‘BMI- for-age’ was significantly lower for older children in Oframase. The z-score of ‘Height-for-age’ showed a small but significant three-way interaction effect among ‘Age’, ‘Gender’, and ‘Village’, F (4, 391) = 3.79, p-value = 0.005, η2 = 0.04. The mean z-score for ‘Height-for-age’ was significantly lower in older children (ages 10-12 years) in all villages except Asakraka. Lower mean z-score for ‘Height-for-age’ in older children (ages 10-12 years) remains to be significant in boys in villages of Awiseasu and Oworobong and in girls in villages of Awiseasu, Miaso and Oframase. Children in isolated communities are at increased risk for lower z-scores in ‘Height-for-age’ and ‘BMI-for-age’. Communities with a clinic, paved road and established infrastructure did not demonstrate evidence of chronic malnutrition. Acute malnutrition in the form of lower z-scores was demonstrated in older children in Oframase. Gender disparities are present and increased awareness of the nutritional status of girls needs to be addressed.Keywords: Nutrition, School children, Ghana, Environmen

NPY1R (neuropeptide Y receptor Y1)

Review on NPY1R (neuropeptide Y receptor Y1), with data on DNA, on the protein encoded, and where the gene is implicated

The tetraspanin TSPAN5 regulates AMPAR exocytosis by interacting with the AP4 complex

Intracellular trafficking of AMPA receptors is a tightly regulated process which involves several adaptor proteins, and is crucial for the activity of excitatory synapses both in basal conditions and during synaptic plasticity. We found that, in rat hippocampal neurons, an intracellular pool of the tetraspanin TSPAN5 promotes exocytosis of AMPA receptors without affecting their internalisation. TSPAN5 mediates this function by interacting with the adaptor protein complex AP4 and Stargazin and possibly using recycling endosomes as a delivery route. This work highlights TSPAN5 as a new adaptor regulating AMPA receptor trafficking

The DNA repair protein ATM as target in autism spectrum disorder

Impairment of GABAergic system has been reported in epilepsy, autism, ADHD and schizophrenia. We recently demonstrated that Ataxia Telangiectasia Mutated (ATM) shapes directly the development of GABAergic system. Here, we show for the first time how the abnormal expression of ATM impacts the pathological condition of autism. We exploit two different animal models of autism, the Mecp2y/- mouse model of Rett syndrome, and mice prenatally exposed to valproic acid, and found increased ATM levels. Accordingly, the treatment with the specific ATM kinase inhibitor KU55933 (KU) normalises molecular, functional and behavioural defects in these mouse models such as the i) delayed GABAergic development, ii) hippocampal hyper-excitability, iii) low cognitive performances, iv) social impairments. Mechanistically, we demonstrate that KU administration to wild type hippocampal neurons leads to i) higher Egr4 activity on Kcc2b promoter, ii) increased expression of Mecp2, iii) potentiated GABA-transmission. These results provide evidences and molecular substrates for the pharmacological development of ATM inhibition in autism spectrum disorders

The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition

RAB39B is a member of the RAB family of small GTPases that controls intracellular vesicular trafficking in a compartment-specific manner. Mutations in the RAB39B gene cause intellectual disability comorbid with autism spectrum disorder and epilepsy, but the impact of RAB39B loss of function on synaptic activity is largely unexplained. Here we show that protein interacting with C-kinase 1 (PICK1) is a downstream effector of GTP-bound RAB39B and that RAB39B-PICK1 controls trafficking from the endoplasmic reticulum to the Golgi and, hence, surface expression of GluA2, a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). The role of AMPARs in synaptic transmission varies depending on the combination of subunits (GluA1, GluA2 and GluA3) they incorporate. RAB39B downregulation in mouse hippocampal neurons skews AMPAR composition towards non GluA2-containing Ca(2+)-permeable forms and thereby alters synaptic activity, specifically in hippocampal neurons. We posit that the resulting alteration in synaptic function underlies cognitive dysfunction in RAB39B-related disorders

TSPAN5 Enriched Microdomains Provide a Platform for Dendritic Spine Maturation through Neuroligin-1 Clustering

Tetraspanins are a class of evolutionarily conserved transmembrane proteins with 33 members identified in mammals that have the ability to organize specific membrane domains, named tetraspanin-enriched microdomains (TEMs). Despite the relative abundance of different tetraspanins in the CNS, few studies have explored their role at synapses. Here, we investigate the function of TSPAN5, a member of the tetraspanin superfamily for which mRNA transcripts are found at high levels in the mouse brain. We demonstrate that TSPAN5 is localized in dendritic spines of pyramidal excitatory neurons and that TSPAN5 knockdown induces a dramatic decrease in spine number because of defects in the spine maturation process. Moreover, we show that TSPAN5 interacts with the postsynaptic adhesion molecule neuroligin-1, promoting its correct surface clustering. We propose that membrane compartmentalization by tetraspanins represents an additional mechanism for regulating excitatory synapses