ABSTRACT
Autism spectrum disorders (ASDs) are a group of devastating neurodevelopmental syndromes that affect up to 1 in 68 children. Despite advances in the identification of ASD risk genes, the mechanisms underlying ASDs remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASDs. Here we investigate the function of Cntnap2 and undertake pharmacological screens to identify phenotypic suppressors. We find that zebrafish cntnap2 mutants display GABAergic deficits, particularly in the forebrain, and sensitivity to drug-induced seizures. High-throughput behavioral profiling identifies nighttime hyperactivity in cntnap2 mutants, while pharmacological testing reveals dysregulation of GABAergic and glutamatergic systems. Finally, we find that estrogen receptor agonists elicit a behavioral fingerprint anti-correlative to that of cntnap2 mutants and show that the phytoestrogen biochanin A specifically reverses the mutant behavioral phenotype. These results identify estrogenic compounds as phenotypic suppressors and illuminate novel pharmacological pathways with relevance to autism.
Subject(s)
Autistic Disorder/drug therapy , Estrogens/pharmacology , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Membrane Proteins/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Animals , Animals, Genetically Modified , Autistic Disorder/genetics , Disease Models, Animal , Estrogens/therapeutic use , Genistein/pharmacology , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , Larva , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Motor Activity/drug effects , Motor Activity/genetics , Phenotype , Phytoestrogens/pharmacology , Psychotropic Drugs/pharmacology , Psychotropic Drugs/therapeutic use , Seizures/drug therapy , Seizures/genetics , Sleep-Wake Transition Disorders/drug therapy , Sleep-Wake Transition Disorders/genetics , Vesicular Glutamate Transport Protein 2/genetics , Vesicular Glutamate Transport Protein 2/metabolism , ZebrafishABSTRACT
OBJECTIVES: The differential diagnosis between iron deficiency anaemia (IDA) and anaemia of chronic disease (ACD) with or without associated iron deficiency can be challenging. We assessed the use of different parameters, both classical like ferritin, transferrin saturation and stainable bone marrow iron stores, and novel markers such as low haemoglobin density (LHD) and hepcidin to help discriminate between the three entities. This would allow the detection of patients with ACD with associated iron deficiency, which could benefit from iron supplementation that would have otherwise remained undetected. MATERIALS AND METHODS: Prospective and observational cohort study from 2012 to 2013 where 200 anaemic cardiac surgical patients were recruited and 165 were studied. Detailed blood and bone marrow analyses were performed to establish the aetiology of anaemia. RESULTS: Seventy-four patients (44.8%) had ACD and 29 (39%) of these had an elevated LHD indicating concomitant iron deficiency. Hepcidin was inappropriately normal or increased in the IDA and ACD group. Mean hepcidin was however lower in the group with IDA (4.8 ng/mL) than in the ACD group (15.0 ng/mL; p=0.002). Median hepcidin was lower in patients with ACD and iron restriction as indicated by LHD >4% (17.5 ng/mL) than on those with no iron restriction (25.9 ng/mL; p=0.045). In patients with ACD there was no concordance between Perl's stain and LHD. CONCLUSIONS: LHD was superior to hepcidin and bone marrow iron stores in identifying patients with ACD and associated iron deficiency, which would potentially benefit from parenteral iron therapy.