Neurobehavioral Testing in Prion Disease Studies

The prion diseases are neurodegenerative diseases characterized by progressive neurocognitive decline and terminal dementia. In this review, we will discuss the role of neurobehavioral testing in mammalian prion disease model systems, including (1) a review of the clinical phenotype of the major prion diseases in natural disease, (2) an evidence-based summary of the benefits and shortcomings of commonly used behavioral assays, and (3) a review of the neurobehavioral testing in rodent prion models. Based upon this review, and in light of the established importance of model systems in studies of prion pathogenesis and the proven role of behavioral testing in nonprion disease neurodegenerative diseases, it is vital that prion researchers consider the clinical consequences of prion infection so as to maximize the impact of their work

Tracheostomy Following Surgery for Congenital Heart Disease: 14-year Institutional Experience

Background: Tracheostomy following congenital heart disease (CHD) surgery is a rare event and associated with significant mortality. Hospital survival has been reported from 20% to 40%. Late mortality for these patients is not well characterized. Methods: We performed a retrospective observational study of patients who had a tracheostomy following CHD surgery (excluding isolated patent ductus arteriosus ligation) between January 2000 and December 2013. Patients were categorized into single-ventricle or biventricular physiology groups. Demographics, genetic syndromes, pulmonary disease, and comorbidities were collected. Outcomes including hospital survival, long-term survival, and weaning from positive pressure ventilation are reported. Bivariate and time-to-event models were used. Results: Over a 14-year period, 61 children (0.9% incidence) had a tracheostomy placed following CHD surgery. There were 12 single-ventricle patients and 49 biventricular patients. Prematurity, genetic syndromes, lung/airway disease, and other comorbidities were common in both CHD groups. Gastrostomy tubes were used more frequently in biventricular physiology patients (91.8%) versus single-ventricle patients (66.7%, P = .04). Survival to hospital discharge was 50% in the single-ventricle group compared to 86% in biventricular patients (P = .01). Long-term survival continued to be poor in the single-ventricle group comparatively (three years, 27.8% vs 64.8%, P = .01). Gastrostomy tube placement was independently associated with survival in both groups (P = .002). Conclusion: Tracheostomy is performed following many types of surgery for CHD and is commonly associated with other comorbidities. Both hospital and long-term survival are substantially lower in children with single-ventricle physiology as compared to patients with biventricular physiology

Extubation Failure after Neonatal Cardiac Surgery: A Multicenter Analysis

Objectives To describe the epidemiology of extubation failure and identify risk factors for its occurrence in a multicenter population of neonates undergoing surgery for congenital heart disease. Study design We conducted a prospective observational study of neonates ≤30 days of age who underwent cardiac surgery at 7 centers within the US in 2015. Extubation failure was defined as reintubation within 72 hours of the first planned extubation. Risk factors were identified with the use of multivariable logistic regression analysis and reported as OR with 95% CIs. Multivariable logistic regression analysis was conducted to examine the relationship between extubation failure and worse clinical outcome, defined as hospital length of stay in the upper 25% or operative mortality. Results We enrolled 283 neonates, of whom 35 (12%) failed their first extubation at a median time of 7.5 hours (range 1-70 hours). In a multivariable model, use of uncuffed endotracheal tubes (OR 4.6; 95% CI 1.8-11.6) and open sternotomy of 4 days or more (OR 4.8; 95% CI 1.3-17.1) were associated independently with extubation failure. Accordingly, extubation failure was determined to be an independent risk factor for worse clinical outcome (OR 5.1; 95% CI 2-13). Conclusions In this multicenter cohort of neonates who underwent surgery for congenital heart disease, extubation failure occurred in 12% of cases and was associated independently with worse clinical outcome. Use of uncuffed endotracheal tubes and prolonged open sternotomy were identified as independent and potentially modifiable risk factors for the occurrence of this precarious complication

Interactive effects of mGlu5 and 5-HT2A receptors on locomotor activity in mice

RationaleMetabotropic glutamate (mGlu) receptors have been suggested to play a role in neuropsychiatric disorders including schizophrenia, drug abuse, and depression. Because serotonergic hallucinogens increase glutamate release and mGlu receptors modulate the response to serotonin (5-HT)(2A) activation, the interactions between serotonin 5-HT(2A) receptors and mGlu receptors may prove to be important for our understanding of these diseases.ObjectiveWe tested the effects of the serotonergic hallucinogen and 5-HT(2A) agonist, 2,5-dimethoxy-4-methylamphetamine (DOM), and the selective 5-HT(2A) antagonist, M100907, on locomotor activity in the mouse behavioral pattern monitor (BPM) in mGlu5 wild-type (WT) and knockout (KO) mice on a C57 background.ResultsBoth male and female mGlu5 KO mice showed locomotor hyperactivity and diminished locomotor habituation compared with their WT counterparts. Similarly, the mGlu5-negative allosteric modulator 2-methyl-6-(phenylethynyl)pyridine (MPEP) also increased locomotor hyperactivity, which was absent in mGlu5 KO mice. The locomotor hyperactivity in mGlu5 receptor KO mice was potentiated by DOM (0.5 mg/kg, subcutaneously (SC)) and attenuated by M100907 (1.0 mg/kg, SC). M100907 (0.1 mg/kg, SC) also blocked the hyperactivity induced by MPEP.ConclusionsThese studies demonstrated that loss of mGlu5 receptor activity either pharmacologically or through gene deletion leads to locomotor hyperactivity in mice. Additionally, the gene deletion of mGlu5 receptors increased the behavioral response to the 5-HT(2A) agonist DOM, suggesting that mGlu5 receptors either mitigate the behavioral effects of 5-HT(2A) hallucinogens or that mGlu5 KO mice show an increased sensitivity to 5-HT(2A) agonists. Taken together, these studies indicate a functional interaction between mGlu5 and 5-HT(2A) receptors

Modeling “psychosis” in vitro by inducing disordered neuronal network activity in cortical brain slices

# The Author(s) 2009. This article is published with open access at Springerlink.com Introduction Dysregulation of neuronal networks has been suggested to underlie the cognitive and perceptual abnor-malities observed schizophrenia. Discussions An in vitro model of psychosis is proposed based on the two different approaches to cause aberrant networ

Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia.

Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress

Glycogen synthase kinase‐3 inhibition rescues sex‐dependent contextual fear memory deficit in human immunodeficiency virus‐1 transgenic mice

BACKGROUND AND PURPOSE: A significant number of HIV‐1 patients on antiretroviral therapy develop HIV‐associated neurocognitive disorders (HAND). Evidence indicate that biological sex may regulate HAND pathogenesis, but the mechanisms remain unknown. We investigated synaptic mechanisms associated with sex differences in HAND, using the HIV‐1‐transgenic 26 (Tg26) mouse model. EXPERIMENTAL APPROACH: Contextual‐ and cue‐dependent memories of male and female Tg26 mice and littermate wild type mice were assessed in a fear conditioning paradigm. Hippocampal electrophysiology, immunohistochemistry, western blot, qRT‐PCR and ELISA techniques were used to investigate cellular, synaptic and molecular impairments. KEY RESULTS: Cue‐dependent memory was unaltered in male and female Tg26 mice, when compared to wild type mice. Male, but not female, Tg26 mice showed deficits in contextual fear memory. Consistently, only male Tg26 mice showed depressed hippocampal basal synaptic transmission and impaired LTP induction in area CA1. These deficits in male Tg26 mice were independent of hippocampal neuronal loss and microglial activation but were associated with increased HIV‐1 long terminal repeat mRNA expression, reduced hippocampal synapsin‐1 protein, reduced BDNF mRNA and protein, reduced AMPA glutamate receptor (GluA1) phosphorylation levels and increased glycogen synthase kinase 3 (GSK3) activity. Importantly, selective GSK3 inhibition using 4‐benzyl‐2‐methyl‐1,2,4‐thiadiazolidine‐3,5‐dione increased levels of synapsin‐1, BDNF and phosphorylated‐GluA1 proteins, restored hippocampal basal synaptic transmission and LTP, and improved contextual fear memory in male Tg26 mice. CONCLUSION AND IMPLICATIONS: Sex‐dependent impairments in contextual fear memory and synaptic plasticity in Tg26 mice are associated with increased GSK3 activity. This implicates GSK3 inhibition as a potential therapeutic strategy to improve cognition in HIV‐1 patients

Putative Kappa Opioid Heteromers As Targets for Developing Analgesics Free of Adverse Effects

It is now generally recognized that upon activation by an agonist, β-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with κ opioid agonists, a series of β-naltrexamides <b>3</b>–<b>10</b> was synthesized in an effort to selectively target putative κ opioid heteromers without recruiting β-arrestin upon activation. The most potent derivative <b>3</b> (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed <b>3</b> to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. <b>3</b> was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of β-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects