Transcriptional reprogramming restores UBE3A brain-wide and rescues behavioral phenotypes in an Angelman syndrome mouse model.

Angelman syndrome (AS) is a neurogenetic disorder caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. The UBE3A gene is paternally imprinted in brain neurons. Clinical features of AS are primarily due to the loss of maternally expressed UBE3A in the brain.

Unique Features of the Gut Microbiome Characterized in Animal Models of Angelman Syndrome.

A large subset of patients with Angelman syndrome (AS) suffer from concurrent gastrointestinal (GI) issues, including constipation, poor feeding, and reflux. AS is caused by the loss of ubiquitin ligase E3A () gene expression in the brain. Clinical features of AS, which include developmental delays, intellectual disability, microcephaly, and seizures, are primarily due to the deficient expression or function of the maternally inherited allele.

Touchscreen cognitive deficits, hyperexcitability and hyperactivity in males and females using two models of Cdkl5 deficiency.

Many neurodevelopmental disorders (NDDs) are the result of mutations on the X chromosome. One severe NDD resulting from mutations on the X chromosome is CDKL5 deficiency disorder (CDD). CDD is an epigenetic, X-linked NDD characterized by intellectual disability (ID), pervasive seizures and severe sleep disruption, including recurring hospitalizations.

An Cell-Based Delivery Platform for Zinc Finger Artificial Transcription Factors in Pre-clinical Animal Models.

Zinc finger (ZF), transcription activator-like effectors (TALE), and CRISPR/Cas9 therapies to regulate gene expression are becoming viable strategies to treat genetic disorders, although effective delivery systems for these proteins remain a major translational hurdle. We describe the use of a mesenchymal stem/stromal cell (MSC)-based delivery system for the secretion of a ZF protein (ZF-MSC) in transgenic mouse models and young rhesus monkeys. Secreted ZF protein from mouse ZF-MSC was detectable within the hippocampus 1 week following intracranial or cisterna magna (CM) injection.

Emerging Gene and Small Molecule Therapies for the Neurodevelopmental Disorder Angelman Syndrome.

Angelman syndrome (AS) is a rare (~1:15,000) neurodevelopmental disorder characterized by severe developmental delay and intellectual disability, impaired communication skills, and a high prevalence of seizures, sleep disturbances, ataxia, motor deficits, and microcephaly. AS is caused by loss-of-function of the maternally inherited UBE3A gene. UBE3A is located on chromosome 15q11-13 and is biallelically expressed throughout the body but only maternally expressed in the brain due to an RNA antisense transcript that silences the paternal copy.

Persistent neuropathology and behavioral deficits in a mouse model of status epilepticus induced by acute intoxication with diisopropylfluorophosphate.

Organophosphate (OP) nerve agents and pesticides are a class of neurotoxic compounds that can cause status epilepticus (SE), and death following acute high-dose exposures. While the standard of care for acute OP intoxication (atropine, oxime, and high-dose benzodiazepine) can prevent mortality, survivors of OP poisoning often experience long-term brain damage and cognitive deficits. Preclinical studies of acute OP intoxication have primarily used rat models to identify candidate medical countermeasures.

Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice.

Background: Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the Na1.1 sodium channel alpha subunit, is one such gene with two co-active promoters.

Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells.

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by impaired communication skills, ataxia, motor and balance deficits, intellectual disabilities, and seizures. The genetic cause of AS is the neuronal loss of UBE3A expression in the brain. A novel approach, described here, is a stem cell gene therapy which uses lentivector-transduced hematopoietic stem and progenitor cells to deliver functional UBE3A to affected cells.

Genetic backgrounds have unique seizure response profiles and behavioral outcomes following convulsant administration.

Three highly utilized strains of mice, common for preclinical genetic studies, were evaluated for seizure susceptibility and behavioral outcomes common to the clinical phenotypes of numerous psychiatric disorders following repeated low-dose treatment with either a gamma-aminobutyric acid (GABA) receptor antagonist (pentylenetetrazole (PTZ)) or a glutamate agonist (kainic acid (KA)). Effects of strain and treatment were evaluated with classic seizure scoring and a tailored behavior battery focused on behavioral domains common in neuropsychiatric research: learning and memory, social behavior, and motor abilities, as well as seizure susceptibility and/or resistance. Seizure response was induced by a single daily treatment of either PTZ (30 mg/kg, intraperitoneally (i.

Cognitive deficits in the Snord116 deletion mouse model for Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is an imprinted neurodevelopmental disease caused by a loss of paternal genes on chromosome 15q11-q13. It is characterized by cognitive impairments, developmental delay, sleep abnormalities, and hyperphagia often leading to obesity. Clinical research has shown that a lack of expression of SNORD116, a paternally expressed imprinted gene cluster that encodes multiple copies of a small nucleolar RNA (snoRNA) in both humans and mice, is most likely responsible for many PWS symptoms seen in humans.

Developmental social communication deficits in the Shank3 rat model of phelan-mcdermid syndrome and autism spectrum disorder.

Unlabelled: Mutations in the SHANK3 gene have been discovered in autism spectrum disorder (ASD), and the intellectual disability, Phelan-McDermid Syndrome. This study leveraged a new rat model of Shank3 deficiency to assess complex behavioral phenomena, unique to rats, which display a richer social behavior repertoire than mice. Uniquely detectable emissions of ultrasonic vocalizations (USV) in rats serve as situation-dependent affective signals and accomplish important communicative functions.

Neuronal overexpression of Ube3a isoform 2 causes behavioral impairments and neuroanatomical pathology relevant to 15q11.2-q13.3 duplication syndrome.

Maternally derived copy number gains of human chromosome 15q11.2-q13.3 (Dup15q syndrome or Dup15q) cause intellectual disability, epilepsy, developmental delay, hypotonia, speech impairments, and minor dysmorphic features.

Germline Chd8 haploinsufficiency alters brain development in mouse.

The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8 mice overlap pathology reported in humans with CHD8 mutations.

Replicable in vivo physiological and behavioral phenotypes of the null mutant mouse model of autism.

Background: Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models.

Touchscreen learning deficits and normal social approach behavior in the Shank3B model of Phelan-McDermid Syndrome and autism.

SHANK3 is a synaptic scaffolding protein localized in the postsynaptic density and has a crucial role in synaptogenesis and neural physiology. Deletions and point mutations in SHANK3 cause Phelan-McDermid Syndrome (PMS), and have also been implicated in autism spectrum disorder (ASD) and intellectual disabilities, leading to the hypothesis that reduced SHANK3 expression impairs basic brain functions that are important for social communication and cognition. Several mouse models of Shank3 deletions have been generated, varying in the specific domain deleted.