Activity Dependent Regulation of Inhibitory Circuitry

Inhibition controls information flow through a neural circuit by modulating synaptic integration, restricting action potentials, and coordinating the activity of ensembles of neurons. These functions are mediated by a diverse array of inhibitory neuron subtypes that synapse on defined domains of a postsynaptic neuron. Activity-dependent transcription controls inhibitory synapse number and function, but how this transcription program affects the inhibitory inputs that form on distinct domains of a neuron remains unclear. We find that behaviorally-driven expression of the transcription factor NPAS4 orchestrates the redistribution of inhibitory synapses made onto a pyramidal neuron, simultaneously promoting inhibitory synapse formation onto the cell body while destabilizing inhibitory synapses formed on the dendrites. This rearrangement of inhibition across a neuron is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (BDNF), which specifically regulates somatic inhibition. These findings suggest that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity.Biology, Molecular and Cellula

A mammalian circadian clock model incorporating daytime expression elements

Models of the mammalian clock have traditionally been based around two feedback loops-the self-repression of Per/Cry by interfering with activation by BMAL/CLOCK, and the repression of Bmal/Clock by the REV-ERB proteins. Recent experimental evidence suggests that the D-box, a transcription factor binding site associated with daytime expression, plays a larger role in clock function than has previously been understood. We present a simplified clock model that highlights the role of the D-box and illustrate an approach for finding maximum-entropy ensembles of model parameters, given experimentally imposed constraints. Parameter variability can be mitigated using prior probability distributions derived from genome-wide studies of cellular kinetics. Our model reproduces predictions concerning the dual regulation of Cry1 by the D-box and Rev-ErbA/ROR response element (RRE) promoter elements and allows for ensemble-based predictions of phase response curves (PRCs). Nonphotic signals such as Neuropeptide Y (NPY) may act by promoting Cry1 expression, whereas photic signals likely act by stimulating expression from the E/E' box. Ensemble generation with parameter probability restraints reveals more about a model's behavior than a single optimal parameter set

Disrupting the circadian clock: Gene-specific effects on aging, cancer, and other phenotypes

The circadian clock imparts 24-hour rhythmicity on gene expression and cellular physiology in virtually all cells. Disruption of the genes necessary for the circadian clock to function has diverse effects, including aging-related phenotypes. Some circadian clock genes have been described as tumor suppressors, while other genes have less clear functions in aging and cancer. In this Review, we highlight a recent study [Dubrovsky et al., Aging 2: 936-944, 2010] and discuss the much larger field examining the relationship between circadian clock genes, circadian rhythmicity, aging-related phenotypes, and cancer

Genetic Controls Balancing Excitatory and Inhibitory Synaptogenesis in Neurodevelopmental Disorder Models

Proper brain function requires stringent balance of excitatory and inhibitory synapse formation during neural circuit assembly. Mutation of genes that normally sculpt and maintain this balance results in severe dysfunction, causing neurodevelopmental disorders including autism, epilepsy and Rett syndrome. Such mutations may result in defective architectural structuring of synaptic connections, molecular assembly of synapses and/or functional synaptogenesis. The affected genes often encode synaptic components directly, but also include regulators that secondarily mediate the synthesis or assembly of synaptic proteins. The prime example is Fragile X syndrome (FXS), the leading heritable cause of both intellectual disability and autism spectrum disorders. FXS results from loss of mRNA-binding FMRP, which regulates synaptic transcript trafficking, stability and translation in activity-dependent synaptogenesis and plasticity mechanisms. Genetic models of FXS exhibit striking excitatory and inhibitory synapse imbalance, associated with impaired cognitive and social interaction behaviors. Downstream of translation control, a number of specific synaptic proteins regulate excitatory versus inhibitory synaptogenesis, independently or combinatorially, and loss of these proteins is also linked to disrupted neurodevelopment. The current effort is to define the cascade of events linking transcription, translation and the role of specific synaptic proteins in the maintenance of excitatory versus inhibitory synapses during neural circuit formation. This focus includes mechanisms that fine-tune excitation and inhibition during the refinement of functional synaptic circuits, and later modulate this balance throughout life. The use of powerful new genetic models has begun to shed light on the mechanistic bases of excitation/inhibition imbalance for a range of neurodevelopmental disease states

Bases moleculares del Sueño

Sleep is vital for all mammals including humans, its distortion implies different health risks and pathologies such as depression, and cardiovascular diseases, and in the end, it can lead to death. In this sense, it is important to find the molecular bases of sleep, among them the genes and their proteins that play a key role in the homeostasis of the living being. Information was collected using the PubMed/Scopus databases in English with a 10-year history using the PICO methodology to determine the words P=Genes, I=Molecular basis, C=Not applicable, O=Sleep. Original articles were determined into two large groups, among these are the "Clock Genes" and other "Genes and Proteins" related to sleep. Among the important clock genes identified are those linked to dopamine (DRD 2) and (DAT 1) and other genes such as pdm3 that participate in the genesis of the innervation of the dopaminergic system and the ANXA3 and 17GAM genes which has shown that overexpression of these is related to sleep deprivation. Understanding the molecular bases of sleep and its gaps still to be studied are key to future studies such as identifying targets and drugs to treat sleep disorders.El sueño es vital para todos los mamíferos incluyendo al ser humano, su distorsión implica diferentes riesgos para la salud y patologías como depresión, enfermedades cardiovasculares y en el extremo puede llevar a la muerte. En ese sentido es de importancia encontrar las bases moleculares del sueño entre ellos los genes y sus proteínas que ejecutan un rol clave en la homeostasis del ser vivo. Se recopiló información utilizando las bases de datos PubMed/Scopus en ingles con 10 años de anterioridad utilizando el protocolo PICO para determinar las palabras P=Genes, I=Base molecular, C=No aplica, O= Sueño. Se determinaron artículos originales en dos grandes grupos entre estos estan los “Genes Reloj” y otros “Genes y Proteínas” relacionados al sueño. Entre los genes reloj de importancia identificados están los vinculados a la dopamina (DRD 2) y el (DAT 1)   y otros genes como el pdm3 que participa en la génesis de la inervación del sistema dopaminérgico y los genes ANXA3 y 17GAM, en la que se ha demostrado que una sobreexpresión de estos se relaciona a la privación del sueño. Entender las bases moleculares del sueño y sus vacíos aun por estudiar son clave para futuros estudios como identificar dianas y drogas para tratar los trastornos del sueño

Kh Domains on Brain Polyribosomes: FMRP and Nova in Translational Regulation

The regulation of protein synthesis is an important aspect of the control of gene expression in neurons and is thought to contribute to neurologic diseases such as Fragile X mental retardation syndrome. We demonstrate that several neuronal RNA-binding proteins implicated in human disease are associated with brain polyribosomes, namely the Nova and Hu paraneoplastic antigens and the Fragile X mental retardation protein. We use microarray analysis of polyribosomal mRNAs in knockout mouse models of these diseases to identify target mRNAs and analyze the translational profiles of mice lacking Nova-1 or FMRP. The KH2 and RGG box RNA-binding domains of FMRP bind specific RNA motifs that form kissing complex and G-quartet structures, respectively. We find that the association of FMRP with polyribosomes in both mouse brain and human neuroblastoma cells is abrogated by competition with kissing complex RNA, but not by high-affinity G-quartet RNA. In addition, the polyribosome associations of FMRP-interacting proteins FXR1 and FXR2, are specifically abrogated by competition with this kissing complex RNA. FXR1 and FXR2 also bind kissing complex RNA via KH2, and they are competed off polyribosomes by kissing complex RNA even in the absence of FMRP. Kissing complex RNA does not disrupt heterodimerization between FMRP and FXR1 or FXR2. We conclude that the mental retardation associated with the I304N mutation, and likely the Fragile-X syndrome more generally, may relate to a crucial role for RNAs harbouring the kissing complex motif as targets for FMRP translational regulation

The role of a group III AQP, AQP11 in intracellular organelle homeostasis

AQP11 is a member of a new aquaporin subfamily which includes many aquaporin homologs with low amino acid identities, around 20% of previously identified AQPs. Although these AQPs have unusual NPA sequences, these AQPs have a completely conserved and functionally indispensable cysteine residue downstream of the second NPA box, suggesting that they belong to a specific AQP subfamily, which we propose to name the group III AQPs. On the other hand, the NPA boxes are highly conserved in previous AQP subfamilies : the group I AQPs, original water-selective aquaporin family and the group II AQPs, aquaglyceroporin family. Currently the roles of the group III AQPs are only known with AQP11 as the disruption of intracellularly located AQP11 in mice produced huge vacuoles in the proximal tubule leading to fatal polycystic kidneys at one month old. This review focused on the classification of AQPs based on primary structures to obtain insights into the function and the role of AQPs. With the accumulation of new AQP-like sequences through genome projects, this classification will be useful to predict their functions as each group may have specific characteristics in its function, distribution and regulation

Identification and characterization of a heme responsive element in the hrg-1 promoter

Despite its biological significance, little is known about how animals sense and respond to heme to maintain homeostasis. C. elegans is a heme auxotroph, which makes it an excellent model to identify and dissect heme homeostasis pathways. Using C. elegans we have identified HRG-1, a vesicular heme transporter that is transcriptionally upregulated when environmental heme is low. The current study seeks to address how hrg-1 is regulated by heme. Here, we show that a putative 23 base pair (bp) heme-responsive element (HRE) and GATA-binding motifs are necessary for heme-dependent regulation of hrg-1. The HRE comprises both enhancer and repressor elements and works in conjunction with ELT-2 to regulate hrg-1 expression. We propose that the HRE could be used as a molecular tool in C. elegans to tightly regulate internal gene expression by modulating environmental heme. Our ultimate goal is to identify the trans-acting factor to eventually create a whole animal sensor for monitoring organismal heme homeostasis