Electrographic spikes are common in wildtype mice.

High-voltage rhythmic electroencephalographic (EEG) spikes have been recorded in wildtype (WT) rats during periods of light slow-wave sleep and passive wakefulness. The source of this activity is unclear but has been attributed to either an inherent form of absence epilepsy or a normal feature of rodent sleep EEG. In contrast, little is known about epileptiform spikes in WT mice. We thus characterize and quantify epileptiform discharges in WT mice for the first time. Thirty-six male WT C57 mice with 24-h wireless telemetry video-EEG recordings were manually scored by blinded reviewers to mark individual spikes and spike trains. Epileptiform spikes were detected in 100% of the recorded WT mice, and spike trains of at least three spikes were recorded in 90% of mice. The spikes were more frequent during the day than at night and were inversely correlated to each animal's locomotor activity. However, the discharges were not absent during active nighttime periods. These discharges may indicate a baseline tendency toward epileptic seizures or perhaps are benign variants of normal rodent background EEG. Nevertheless, a better understanding of baseline WT EEG activity will aid in differentiating pathological and normal EEG activity in mouse epilepsy models.

Replicable in vivo physiological and behavioral phenotypes of the Shank3B 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. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice. METHODS: In vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant (Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays. RESULTS: Relative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory. CONCLUSIONS: Robust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong evidence for robustness and replicability of key translational phenotypes in Shank3B mutant mice and support the usefulness of this mouse model of ASD for therapeutic discovery.

An 8-year old boy with continuous spikes and waves during slow sleep presenting with positive onconeuronal antibodies.

OBJECTIVE: To determine the etiology of epilepsy with continuous spikes and waves during slow sleep (CSWS)/electrical status epilepticus during sleep (ESES) in an 8-year old boy with a history of neuroblastoma and opsoclonus-myoclonus. MATERIAL & METHODS: A combination of clinical characterization and follow-up, video EEG and laboratory investigations. RESULTS: We report the case of an 8-year old boy with a history of neuroblastoma and opsoclonus-myoclonus, who presented with intellectual disability, pharmacotherapy-resistant epilepsy and CSWS/ESES. Although the patient's neuroblastoma had been successfully treated 8 years prior to presentation and an extensive workup did not show a tumor reoccurrence, testing for onconeuronal antibodies was positive for anti-Ma2 and anti-CV2/CRMP5 antibodies. High-dose intravenous methylprednisolone and a taper of oral methylprednisolone were given, leading to a significant clinical improvement. During the taper the patient's condition and EEG manifestations deteriorated again necessitating another cycle of steroid therapy, which lead to a stable improvement. During a 6-month follow-up no CSWS/ESES was seen on EEG and anti-Ma2 and anti-CV2/CRMP5 antibodies remained undetectable. CONCLUSION: This case suggests that onconeuronal antibodies may be involved in the pathogenesis of CSWS/ESES.

A vascular model of Tsc1 deficiency accelerates renal tumor formation with accompanying hemangiosarcomas.

UNLABELLED: Tuberous sclerosis complex (TSC) is an autosomal disease caused by inactivating mutations in either of the tumor suppressor genes TSC1 or TSC2. TSC-associated tumor growth is present in multiple tissues and organs including brain, kidney, liver, heart, lungs, and skin. In the kidney, TSC angiomyolipomas have aberrant vascular structures with abnormal endothelial cells, suggesting a role for endothelial mTORC1 function. In the current report, a genetically engineered mouse model (GEMM) with a conditional knockout allele of Tsc1 with a Darpp32-Cre allele displayed accelerated formation of both kidney cystadenomas and paw hemangiosarcomas. All mutant mice developed hemangiosarcomas on multiple paws by 6 weeks of age. By 16 weeks of age, the average mutant hind paw was 4.0 mm in diameter, nearly double the size of control mice. Furthermore, the hemangiosarcomas and kidney cystadenomas were responsive to intraperitoneal rapamycin treatment. Immunoblotting and immunostaining for phospho-S6 (pS6) and phospho-CAD showed that the effect of rapamycin on tumor size was through inhibition of the mTOR signaling pathway. Finally, elevated VEGF mRNA levels were also observed in hemangiosarcoma specimens. Because paw hemangiosarcomas are easily detectable and scorable for size and growth, this novel mouse model enables accelerated in vivo drug testing for therapies of TSC-related tumors. IMPLICATIONS: These findings provide a strong rationale for simultaneous use of this conditional knockout mouse as an in vivo genetic model while seeking new cancer therapies for TSC-related tumors.