Search results for "PPO"
showing 10 items of 5642 documents
Shank3 Mice Carrying the Human Q321R Mutation Display Enhanced Self-Grooming, Abnormal Electroencephalogram Patterns, and Suppressed Neuronal Excitab…
2019
Shank3, a postsynaptic scaffolding protein involved in regulating excitatory synapse assembly and function, has been implicated in several brain disorders, including autism spectrum disorders (ASD), Phelan-McDermid syndrome, schizophrenia, intellectual disability, and mania. Here we generated and characterized a Shank3 knock-in mouse line carrying the Q321R mutation (Shank3Q321R mice) identified in a human individual with ASD that affects the ankyrin repeat region (ARR) domain of the Shank3 protein. Homozygous Shank3Q321R/Q321R mice show a selective decrease in the level of Shank3a, an ARR-containing protein variant, but not other variants. CA1 pyramidal neurons in the Shank3Q321R/Q321R hip…
Deciphering Alzheimer’s Disease Pathogenic Pathway: Role of Chronic Brain Hypoperfusion on p-Tau and mTOR
2021
This review examines new biomolecular findings that lend support to the hemodynamic role played by chronic brain hypoperfusion (CBH) in driving a pathway to Alzheimer’s disease (AD). CBH is a common clinical feature of AD and the current topic of intense investigation in AD models. CBH is also the basis for the vascular hypothesis of AD which we originally proposed in 1993. New biomolecular findings reveal the interplay of CBH in increasing tau phosphorylation (p-Tau) in the hippocampus and cortex of AD mice, damaging fast axonal transport, increasing signaling of mammalian target of rapamycin (mTOR), impairing learning-memory function, and promoting the formation of neurofibrillary tangles…
Chronic Stress Modulates Interneuronal Plasticity: Effects on PSA-NCAM and Perineuronal Nets in Cortical and Extracortical Regions.
2018
Chronic stress has an important impact on the adult brain. However, most of the knowledge on its effects is focused on principal neurons and less on inhibitory neurons. Consequently, recent reports have begun to describe stress-induced alterations in the structure, connectivity and neurochemistry of interneurons. Some of these changes appear to be mediated by certain molecules particularly associated to interneurons, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) and components of the perineuronal nets (PNN), specialized regions of the extracellular matrix. These plasticity-related molecules modulate interneuronal structure and connectivity, particularly of …
MicroRNA-22 Controls Aberrant Neurogenesis and Changes in Neuronal Morphology After Status Epilepticus
2018
Prolonged seizures (status epilepticus, SE) may drive hippocampal dysfunction and epileptogenesis, at least partly, through an elevation in neurogenesis, dysregulation of migration and aberrant dendritic arborization of newly-formed neurons. MicroRNA-22 was recently found to protect against the development of epileptic foci, but the mechanisms remain incompletely understood. Here, we investigated the contribution of microRNA-22 to SE-induced aberrant adult neurogenesis. SE was induced by intraamygdala microinjection of kainic acid (KA) to model unilateral hippocampal neuropathology in mice. MicroRNA-22 expression was suppressed using specific oligonucleotide inhibitors (antagomir-22) and ne…
Maternal Caloric Restriction Implemented during the Preconceptional and Pregnancy Period Alters Hypothalamic and Hippocampal Endocannabinoid Levels a…
2016
Journal Article; Exposure to inadequate nutritional conditions in critical windows of development has been associated to disturbances on metabolism and behavior in the offspring later in life. The role of the endocannabinoid system, a known regulator of energy expenditure and adaptive behaviors, in the modulation of these processes is unknown. In the present study, we investigated the impact of exposing rat dams to diet restriction (20% less calories than standard diet) during pre-gestational and gestational periods on: (a) neonatal outcomes; (b) endocannabinoid content in hypothalamus, hippocampus and olfactory bulb at birth; (c) metabolism-related parameters; and (d) behavior in adult mal…
A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis
2018
The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis. A randomized, double-blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score [NAS] ≥4, and liver fibrosis (stages 1-3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2-point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis and no worsening of fibrosis; improvement in fibrosis by ≥1 stag…
GRIP1 Binds to ApoER2 and EphrinB2 to Induce Activity-Dependent AMPA Receptor Insertion at the Synapse
2017
Summary Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking in response to neuronal activity is critical for synaptic function and plasticity. Here, we show that neuronal activity induces the binding of ephrinB2 and ApoER2 receptors at the postsynapse to regulate de novo insertion of AMPA receptors. Mechanistically, the multi-PDZ adaptor glutamate-receptor-interacting protein 1 (GRIP1) binds ApoER2 and bridges a complex including ApoER2, ephrinB2, and AMPA receptors. Phosphorylation of ephrinB2 in a serine residue (Ser-9) is essential for the stability of such a complex. In vivo, a mutation on ephrinB2 Ser-9 in mice results in a complete disruption…
Neurochemical Phenotype of Reelin Immunoreactive Cells in the Piriform Cortex Layer II
2016
Reelin, a glycoprotein expressed by Cajal-Retzius neurons throughout the marginal layer of developing neocortex, has been extensively shown to play an important role during brain development, guiding neuronal migration and detachment from radial glia. During the adult life, however, many studies have associated Reelin expression to enhanced neuronal plasticity. Although its mechanism of action in the adult brain remains mostly unknown, Reelin is expressed mainly by a subset of mature interneurons. Here, we confirm the described phenotype of this subpopulation in the adult neocortex. We show that these mature interneurons, although being in close proximity, lack polysialylated neural cell ad…
Cannabinoid Control of Learning and Memory through HCN Channels
2016
The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase, and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of the CB1R-HCN pathway impairs d…
Modulation of brain PUFA content in different experimental models of mice.
2016
International audience; The relative amounts of arachidonic acid (AA) and docosahexaenoic acid (DHA) govern the different functions of the brain. Their brain levels depend on structures considered, on fatty acid dietary supply and the age of animals. To have a better overview of the different models available in the literature we here compared the brain fatty acid composition in various mice models (C57BL/6J, CD1, Fat-1, SAMP8 mice) fed with different n-3 PUFA diets (deficient, balanced, enriched) in adults and aged animals. Our results demonstrated that brain AA and DHA content is 1) structure-dependent; 2) strain-specific; 3) differently affected by dietary approaches when compared to gen…