Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.

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.

Circadian clock gene polymorphisms and sleep-wake disturbance in Alzheimer disease.

OBJECTIVES: One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes. DESIGN: One week of ad libitum ambulatory sleep data collection. SETTING: At-home collection of sleep data and in-laboratory questionnaire. PARTICIPANTS: Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer's Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer's Disease Neuroimaging Initiative data set. MEASUREMENTS: Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined. RESULTS: Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance. CONCLUSIONS: It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD.

Parasomnías: fenómenos episódicos del sueño / Parasomnias: episodic phenomena during sleep

Las parasomnias consisten en fenómenos episódicos del sueño caracterizados por una activación del SNC que involucra al soma a través de las vías motoras y /o al sistema nerviosos vegetativo o a las funciones psíquicas. La prevalencia de las parasomnias es mayor en edad pediátrica, lo que sugiere que factores madurativos y del desarrollo son importantes en su etiología. El diagnóstico se basa en la historia clínica y de sueño; en la exploración neurológica y neuropsicología; y en el registro vídeo EEG- polisomnográfico. Las parasomnias se dividen en cuatro grupo atendiendo al periodo de sueño en el que aparecen; transición vigilia-sueño, sueño NREM, sueño REM y despertar. El registro EEG de las parasomnias muestra una combinación de frecuencias alfa, theta y delta, sin un patrón típico de vigilia. El registro vídeo- EEG-PSG demuestra en muchos casos el factor desencadenante de la parasomnia: apnea obstructiva, reflujo gastro-esofágico, movimientos periódicos de las piernas, etc. El diagnóstico diferencial con las crisis epilépticas se basa en: a) presencia de crisis diurnas y nocturnas en la epilepsia; b) la semiología electroclínica; c) la aparición de anomalías paroxísticas intercríticas o críticas en el EEG; y d) la respuesta al tratamiento anticomicial. Las parasomnias provocan fragmentación y escasa eficiencia del sueño. Durante el día aparecen síntomas de somnolencia y trastornos del aprendizaje. La monitorización vídeo-PSG posibilita un diagnóstico de certeza y un tratamiento adecuado (AU)

Parasomnias are episodic phenomena characterized by an activation of the CNS involving the motor and/or autonomic systems, and the psychological functions. The prevalence of parasomnias is high in children suggesting that maturational and developmental factors are of major importance in their etiology. The diagnosis is based on the child´s clinical and sleep history, family history, physical, neurological and neuropsychological examinations and a period during the night; wakefulness-sleep transition, non-REM sleep, REM sleep or arousal. The EEG shows a combination of alpha, theta and delta frequencies without evidence of clear wakefulness. The video-PSG may reveal a trigger: obstructive sleep apnea, gastroesophageal reflux, or periodic leg movements of sleep. The differential diagnosis with an epileptic seizure is based on: <) the presence of nocturnal and diurnal episodes in epilepsy; b) the electroclinical semiology; c) the appearance of interictal and/or ictal discharges on the EEG, d) the response to antiepileptic therapy. Parasomnias provoke a fragmentation of nocturnal sleep and decrease its efficiency. The child will suffer from daytime hypersomnolence and learning difficulties. Video-PSG monitoring will provide and accurate diagnosis and allow adequate therapy (AU)

Parasomnias: co-occurrence and genetics.

In clinical practice, parasomnias are often found to run in families and to co-occur. Several studies have indicated a role of genetic factors in them. In 1990, a questionnaire (response rate, 77%) sent to the Finnish Twin Cohort, a representative population sample aged 33-60 years, surveyed the frequency of five parasomnias (sleepwalking, sleeptalking, enuresis, bruxism, and nightmares) in childhood and as adults. In assessing the phenotypic covariation and shared genetic effects between the parasomnias, we used polychoric correlations and structural equation modelling. In childhood (n = 5856 individuals), co-occurrence is highest in sleeptalking with sleepwalking (R = 0.73), nightmares (R = 0.50), and bruxism (R = 0.43). As adults (n = 8567), the results are similar (R = 0.56, 0.43, and 0.39, respectively). The analyses of shared genetic effects included 815 monozygotic and 1442 dizygotic twin pairs with complete responses on four parasomnias as adults. The strongest genetic covariation was found in sleeptalking with sleepwalking, sleeptalking with bruxism, and in sleeptalking with nightmares. The estimated proportions of shared genetic effects were 50, 30, and 26%, respectively. The present results indicate that parasomnias share some common genetic background.