Dampened α7 nAChR activity contributes to audiogenic seizures and hyperactivity in a mouse model of Fragile X Syndrome.

Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and often accompanied with debilitating pathologies including seizures and hyperactivity. FXS arises from a trinucleotide repeat expansion in the 5' UTR of the gene that silences expression of the RNA-binding protein FMRP. Despite progress in understanding FMRP functions, the identification of effective therapeutic targets has lagged and at present there are no viable treatment options.

Loss of synaptopodin impairs mGluR5 and protein synthesis-dependent mGluR-LTD at CA3-CA1 synapses.

Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is an important form of synaptic plasticity that occurs in many regions of the central nervous system and is the underlying mechanism for several learning paradigms. In the hippocampus, mGluR-LTD is manifested by the weakening of synaptic transmission and elimination of dendritic spines. Interestingly, not all spines respond or undergo plasticity equally in response to mGluR-LTD.

Loss of synaptopodin impairs mGluR5 and protein synthesis dependent mGluR-LTD at CA3-CA1 synapses.

Unlabelled: Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is an important form of synaptic plasticity that occurs in many regions of the CNS and is the underlying mechanism for several learning paradigms. In the hippocampus, mGluR-LTD is manifested by the weakening of synaptic transmission and elimination of dendritic spines. Interestingly, not all spines respond or undergo plasticity equally in response to mGluR-LTD.

Combined DiI and Antibody Labeling Reveals Complex Dysgenesis of Hippocampal Dendritic Spines in a Mouse Model of Fragile X Syndrome.

Structural, functional, and molecular alterations in excitatory spines are a common hallmark of many neurodevelopmental disorders including intellectual disability and autism. Here, we describe an optimized methodology, based on combined use of DiI and immunofluorescence, for rapid and sensitive characterization of the structure and composition of spines in native brain tissue. We successfully demonstrate the applicability of this approach by examining the properties of hippocampal spines in juvenile KO mice, a mouse model of Fragile X Syndrome.

Group I Metabotropic Glutamate Receptor Interacting Proteins: Fine-Tuning Receptor Functions in Health and Disease.

Group I metabotropic glutamate receptors mediate slow excitatory neurotransmission in the central nervous system and are critical to activity-dependent synaptic plasticity, a cellular substrate of learning and memory. Dysregulated receptor signaling is implicated in neuropsychiatric conditions ranging from neurodevelopmental to neurodegenerative disorders. Importantly, group I metabotropic glutamate receptor signaling functions can be modulated by interacting proteins that mediate receptor trafficking, expression and coupling efficiency to signaling effectors.

Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord.

Circuit function in the CNS relies on the balanced interplay of excitatory and inhibitory synaptic signaling. How neuronal activity influences synaptic differentiation to maintain such balance remains unclear. In the mouse spinal cord, a population of GABAergic interneurons, GABApre, forms synapses with the terminals of proprioceptive sensory neurons and controls information transfer at sensory-motor connections through presynaptic inhibition.

Actinin-4 Governs Dendritic Spine Dynamics and Promotes Their Remodeling by Metabotropic Glutamate Receptors.

Dendritic spines are dynamic, actin-rich protrusions in neurons that undergo remodeling during neuronal development and activity-dependent plasticity within the central nervous system. Although group 1 metabotropic glutamate receptors (mGluRs) are critical for spine remodeling under physiopathological conditions, the molecular components linking receptor activity to structural plasticity remain unknown. Here we identify a Ca(2+)-sensitive actin-binding protein, α-actinin-4, as a novel group 1 mGluR-interacting partner that orchestrates spine dynamics and morphogenesis in primary neurons.

Quantitative profiling of brain lipid raft proteome in a mouse model of fragile X syndrome.

Fragile X Syndrome, a leading cause of inherited intellectual disability and autism, arises from transcriptional silencing of the FMR1 gene encoding an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). FMRP can regulate the expression of approximately 4% of brain transcripts through its role in regulation of mRNA transport, stability and translation, thus providing a molecular rationale for its potential pleiotropic effects on neuronal and brain circuitry function. Several intracellular signaling pathways are dysregulated in the absence of FMRP suggesting that cellular deficits may be broad and could result in homeostatic changes.

Agonist-dependent signaling by group I metabotropic glutamate receptors is regulated by association with lipid domains.

Group I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, play critical functions in forms of activity-dependent synaptic plasticity and synapse remodeling in physiological and pathological states. Importantly, in animal models of fragile X syndrome, group I mGluR activity is abnormally enhanced, a dysfunction that may partly underlie cognitive deficits in the condition. Lipid rafts are cholesterol- and sphingolipid-enriched membrane domains that are thought to form transient signaling platforms for ligand-activated receptors.

Identification of GPCR localization in detergent resistant membranes.

Lipid domains of the plasma membrane were originally described as a cell matrix insoluble in cold -nonionic detergents and enriched in glycosphingolipids. Because of these biochemical properties, these membrane domains were termed detergent-resistant membranes (DRMs) or detergent-insoluble -glycolipid-enriched (DIG) membranes. Membrane rafts and caveolae are two types of lipid domains that share these properties, as well as structural/functional dependence on membrane cholesterol.

Caveolin-1 knockout mice exhibit impaired induction of mGluR-dependent long-term depression at CA3-CA1 synapses.

Group I metabotropic glutamate receptors (mGluR1/5) are important to synaptic circuitry formation during development and to forms of activity-dependent synaptic plasticity. Dysregulation of mGluR1/5 signaling is implicated in some disorders of neurodevelopment, including fragile X syndrome, the most common inherited form of intellectual disabilities and leading cause of autism. Site(s) in the intracellular loops of mGluR1/5 directly bind caveolin-1, an adaptor protein that associates with membrane rafts.

Long-term effects of upgrading to biventricular pacing: differences with cardiac resynchronization therapy as primary indication.

Background: Few studies have assessed the long-term effects of cardiac resynchronization therapy (CRT) in patients with advanced heart failure (HF) and previously right ventricular apical pacing (RVAP).

Aims: To assess the clinical and hemodynamic impact of upgrading to biventricular pacing in patients with severe HF and permanent RVAP in comparison with patients who had CRT implantation as initial therapy.

Methods And Results: Thirty-nine patients with RVAP, advanced HF (New York Heart Association [NYHA] III-IV), and severe depression of left ventricular ejection fraction (LVEF) were upgraded to biventricular pacing (group A).

Electro-anatomical mapping in a patient with isolated left ventricular non-compaction and left ventricular tachycardia.

We report the case of a 59-year-old non-Caucasian man with sustained left ventricular (LV) tachycardia and isolated LV non-compaction. An electro-anatomical mapping of the right ventricle and LV with the Carto system was reconstructed. The voltage map excluded the presence of scarred tissue as a possible substrate responsible of the ventricular arrhythmia.

Regulation of group I metabotropic glutamate receptor trafficking and signaling by the caveolar/lipid raft pathway.

Endocytic trafficking of neurotransmitter receptors is critical to neuronal signaling and activity-dependent synaptic plasticity. Although the importance of clathrin-mediated endocytosis in receptor trafficking in neurons is well established, the contribution of the caveolar/lipid raft pathway has been little explored. Here, we show that caveolin-1, an adaptor protein that associates with lipid rafts and the main coat protein of caveolae, binds to and colocalizes with metabotropic glutamate receptors 1/5 (mGluR1/5).

Leaving out control groups: an internal contrast analysis of gene expression profiles in atrial fibrillation patients--a systems biology approach to clinical categorization.

Atrial fibrillation (AF) is a frequent chronic dysrythmia with an incidence that increases with age (>40). Because of its medical and socio-economic impacts it is expected to become an increasing burden on most health care systems. AF is a multi-factorial disease for which the identification of subtypes is warranted.

Proteomic analysis reveals novel binding partners of metabotropic glutamate receptor 1.

Regulated trafficking of neurotransmitter receptors is critical to normal neurodevelopment and neuronal signaling. Group I mGluRs (mGluR1/5 and their splice variants) are G protein-coupled receptors enriched at excitatory synapses, where they serve to modulate glutamatergic transmission. The mGluR1 splice variants mGluR1a and mGluR1b are broadly expressed in the central nervous system and differ in their signaling and trafficking properties.

The ups and downs of translation-dependent plasticity.

Neuroscientists have been looking for good examples linking neuronal activity to gene expression/regulation involved in synaptic plasticity and the formation of long-term memories. New findings from Park et al. and Waung et al.

Persistent left superior vena cava in patients treated with His-bundle pacing: trouble or help?

We describe a case of a 50-year-old man with advanced atrioventricular block treated successfully with His-bundle pacing via a persistent left superior vena cava draining into the coronary sinus.

Postsynaptic density protein-95 regulates NMDA channel gating and surface expression.

NMDA receptors (NMDARs) colocalize with postsynaptic density protein-95 (PSD-95), a multivalent synaptic scaffolding protein and core component of the postsynaptic density, at excitatory synapses. Although much is known about the identity and properties of scaffolding proteins, little is known about their actions on NMDAR function. Here we show that association of PSD-95 with NMDARs modulates channel gating and surface expression.

Divalent cations modulate the activity of metabotropic glutamate receptors.

Metabotropic glutamate receptors (mGluRs) and calcium receptors (CaR) are closely related G protein-coupled receptors (GPCRs). The similar structural and functional properties of mGluRs and CaRs include conserved amino acid residues involved in glutamate binding in mGluRs and Ca2+ binding in the CaR. Furthermore, recent findings have demonstrated that mGluRs can respond to high extracellular Ca2+ (Ca2+(o)) whereas CaR activity is potentiated by L-amino acids.

Thyrotropin effects on ultraviolet radiation-dependent apoptosis in FRTL-5 cells.

Apoptosis plays an important role within the endocrine system, particularly in the thyroid gland, although little is known about its regulation in normal thyroids. Because thyrotropin (TSH) regulates many thyroid-specific functions and cell proliferation, we investigated whether TSH can influence such mechanisms. To induce apoptosis we used UV-C radiation.

Alternative splicing unmasks dendritic and axonal targeting signals in metabotropic glutamate receptor 1.

Precise targeting of neurotransmitter receptors to different neuronal compartments is a fundamental step for the establishment and function of synaptic circuitry. Group I metabotropic glutamate receptors, mGluR1 and mGluR5, control glutamatergic neurotransmission by acting both postsynaptically and presynaptically. Four alternatively spliced variants of the mGluR1 gene exist, which differ in their signaling properties and subcellular localization.