The spectrum of epilepsy and electroencephalographic abnormalities due to <i><scp>SHANK</scp>3</i> loss‐of‐function mutations

Holder, J. Lloyd; Quach, Michael

doi:10.1111/epi.13506

Cited by 66 publications

(77 citation statements)

References 28 publications

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“…For example, enhanced EEG gamma oscillatory power has been reported across a number of genetic mouse ASD models, consistent with resting state EEG findings in individuals with neurodevelopmental disorders [31, 60, 61]. Such examples include increased gamma power in both Mecp2 and Pten mutant mouse models [62, 63].…”

Section: Discussionmentioning

confidence: 58%

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

et al. 2017

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BackgroundAutism 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.MethodsIn 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.ResultsRelative 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.ConclusionsRobust 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...

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Section: Discussionmentioning

confidence: 58%

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

et al. 2017

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“…Lennox–Gastaut syndrome most often follows other types of pharmacoresistant epilepsies including infantile spasms, late‐onset spasms, or myoclonic astatic epilepsy. SHANK3 loss‐of‐function or deletion – common in Phelan–McDermid syndrome – begins with Lennox–Gastaut syndrome in up to 20% of cases …”

Section: Gene Dysfunction In Age‐dependent Epilepsy Phenotypesmentioning

confidence: 99%

“…SHANK3 loss-of-function or deletioncommon in Phelan-McDermid syndromebegins with Lennox-Gastaut syndrome in up to 20% of cases. 47…”

Section: Lennox-gastaut Syndromementioning

confidence: 99%

Gene mutations in paediatric epilepsies cause NMDA‐pathy, and phasic and tonic GABA‐pathy

Gataullina

Bienvenu

Nabbout

et al. 2019

Develop Med Child Neuro

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The aim of this study was to disentangle mechanisms of epileptogenesis in monogenic epilepsies in children. We reviewed paediatric monogenic epilepsies excluding brain malformation or an inborn error of metabolism, but including the gene function whether there is loss‐of‐function or gain‐of‐function, age at gene expression when available, and associated epilepsy syndrome. Genes for which at least five patients with similar epilepsy phenotype had been reported were selected. Three mechanisms are shared by most monogenic epilepsies: (1) excess of N‐methyl‐d‐aspartate (NMDA) transmission activation (NMDA‐pathies); (2) abnormal gamma‐aminobutyric acid (GABA) transmission with reduced inhibition (phasic GABA‐pathies); and (3) tonic activation of extrasynaptic GABAA receptors by extracellular GABA (tonic GABA‐pathies). NMDA‐pathies comprise early epileptic encephalopathy with suppression‐burst, neonatal/infantile benign seizures, West and Lennox–Gastaut syndromes, and encephalopathy with continuous spike waves in slow sleep, thus brief seizures with major interictal spiking. Phasic GABA‐pathies comprise mostly generalized epilepsy with febrile seizures plus and Dravet syndrome, thus long‐lasting seizures with mild interictal spiking. Tonic GABA‐pathies cause epilepsy with myoclonic–atonic seizures and Angelman syndrome, thus major high‐amplitude slow‐wave activity. This pathophysiological approach to monogenic epilepsies provides diagnostic clues and helps to guide treatment strategy. What this paper adds In paediatric monogenic epilepsies, electroclinical patterns point to three main mechanisms: NMDA‐pathies, and phasic and tonic GABA‐pathies. Antiepileptic treatment choice could be guided by each of these mechanisms.

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“…Gene repair or IGF1 interventions can restore excitatory synaptic transmission. It has been suggested that deletions in the SHANK3 gene could possibly mediate the mechanism of epileptic seizures by causing a decrease in excitatory synaptic function …”

Section: Ipsc Studies On the Molecular Mechanisms Of Gementioning

confidence: 99%

“…It has been suggested that deletions in the SHANK3 gene could possibly mediate the mechanism of epileptic seizures by causing a decrease in excitatory synaptic function. [70][71][72][73] Multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2), characterized by epilepsy, myoclonus, and mental retardation, 74 can be caused by mutations in another membrane protein gene, the phosphatidylinositol glycan class A gene (PIGA), which encodes a phosphatidylinositol glycan class A protein (PIGA), one of the phospholipid elements of the cell membrane. Yuan et al 75 found that iPSCs from patients with PIGA mutations (c.1234C>T) exhibit lower proliferative capacity than normal heterozygotes, fewer induced GABAergic neurons with low maturation levels, aberrant synapse formation, and abnormal membrane depolarization.…”

Section: Mutations Affecting Neurite Maturationmentioning

confidence: 99%

Progress in the molecular mechanisms of genetic epilepsies using patient‐induced pluripotent stem cells

et al. 2018

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SummaryResearch findings on the molecular mechanisms of epilepsy almost always originate from animal experiments, and the development of induced pluripotent stem cell (iPSC) technology allows the use of human cells with genetic defects for studying the molecular mechanisms of genetic epilepsy (GE) for the first time. With iPSC technology, terminally differentiated cells collected from GE patients with specific genetic etiologies can be differentiated into many relevant cell subtypes that carry all of the GE patient's genetic information. iPSCs have opened up a new research field involving the pathogenesis of GE. Using this approach, studies have found that gene mutations induce GE by altering the balance between neuronal excitation and inhibition, which is associated. among other factors, with neuronal developmental disturbances, ion channel abnormalities, and synaptic dysfunction. Simultaneously, astrocyte activation, mitochondrial dysfunction, and abnormal signaling pathway activity are also important factors in the molecular mechanisms of GE.

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The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss‐of‐function mutations

Cited by 66 publications

References 28 publications

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

Gene mutations in paediatric epilepsies cause NMDA‐pathy, and phasic and tonic GABA‐pathy

Progress in the molecular mechanisms of genetic epilepsies using patient‐induced pluripotent stem cells

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