Monogenic models of absence epilepsy

Maheshwari, Atul; Noebels, Jeffrey L.

doi:10.1016/b978-0-444-63326-2.00012-0

Cited by 65 publications

(41 citation statements)

References 128 publications

(135 reference statements)

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“…First, they had numerous spike-wave discharges (SWDs) that 302 typically were 3-6 Hz and lasted 1-2 s (Figure 3C,E,F). These oscillations showed similar 303 characteristics to those generalized spike-wave discharges observed in animal models of absence 304 seizures (Depaulis and Charpier, 2018;Maheshwari and Noebels, 2014). A much smaller 305 number of SWDs with similar characteristics were also observed in WT mice (Figure 3B), 306 consistent with previous studies (Arain et al, 2012;Letts et al, 2014).…”

Section: Cortical Hyperexcitability and Epileptic Seizures In Stxbp1 supporting

confidence: 80%

Stxbp1/Munc18-1 haploinsufficiency in mice recapitulates key features of STXBP1 encephalopathy and impairs cortical inhibition

Cai

Chao

et al. 2019

Preprint

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150 words) 21 Mutations in genes encoding synaptic proteins cause many neurodevelopmental disorders, but 22 the underlying pathogeneses are poorly understood. Syntaxin-binding protein 1 (STXBP1) is an 23 essential component of the neurotransmitter release machinery. Its de novo heterozygous 24 mutations are among the most frequent causes of neurodevelopmental disorders including 25 intellectual disabilities and epilepsies. These disorders, collectively referred to as STXBP1 26 encephalopathy, affect a broad spectrum of neurological and neuropsychiatric features common 27 among neurodevelopmental disorders. To gain insight into STXBP1 encephalopathy 28 pathogenesis, we generated new Stxbp1 null alleles in mice and found that Stxbp1 29 haploinsufficiency impaired cognitive, psychiatric, and motor functions and caused cortical 30 hyperexcitability and seizures. Surprisingly, Stxbp1 haploinsufficiency reduced 31 neurotransmission from cortical parvalbumin-and somatostatin-expressing GABAergic 32 interneurons by differentially decreasing the synaptic strength and connectivity, respectively. 33 These results demonstrate that Stxbp1 haploinsufficient mice recapitulate key features of 34

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Section: Cortical Hyperexcitability and Epileptic Seizures In Stxbp1 supporting

confidence: 80%

Stxbp1/Munc18-1 haploinsufficiency in mice recapitulates key features of STXBP1 encephalopathy and impairs cortical inhibition

Cai

Chao

et al. 2019

Preprint

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“…Absence seizures are the defining feature of both childhood and juvenile absence epilepsy, and they are also common in juvenile myoclonic epilepsy (Duncan, 1997). All three disorders are genetically determined, yet in most cases, it is impossible to determine which mutations directly contribute to seizures (Maheshwari and Noebels, 2014). During SWD in rats, RT and TC are simultaneously excited by synchronous, transient cortical input (Danober et al, 1998; Pinault, 2003; Polack and Charpier, 2006).…”

Section: Thalamic Contributions To Widespread Oscillationsmentioning

confidence: 99%

“…Absence seizures detected using MEG and analyzed to extrapolate signals from deep sources report early activity in both frontal cortex and thalamus (Tenney et al, 2013). Precise onset location and propagation pattern vary from patient to patient, which may reflect the diverse, and often unexplained, genetic causes of absence epilepsy (Maheshwari and Noebels, 2014). Consistent early activation in frontal cortex and thalamus (Tenney et al, 2013) suggests that human absence seizures may also originate from a focal network origin despite heterogeneous genetic causes.…”

Section: Thalamic Contributions To Widespread Oscillationsmentioning

confidence: 99%

Tapping the Brakes: Cellular and Synaptic Mechanisms that Regulate Thalamic Oscillations

Fogerson

Huguenard

2016

Neuron

129

135

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Thalamic oscillators contribute to both normal rhythms associated with sleep and anesthesia and abnormal, hypersynchronous oscillations that manifest behaviorally as absence seizures. In this review, we highlight new findings that refine thalamic contributions to cortical rhythms and suggest that thalamic oscillators may be subject to both local and global control. We describe endogenous thalamic mechanisms that limit network synchrony and discuss how these protective brakes might be restored to prevent absence seizures. Finally, we describe how intrinsic and circuit-level specializations among thalamocortical loops may determine their involvement in widespread oscillations and render subsets of thalamic nuclei especially vulnerable to pathological synchrony.

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“…Nevertheless it is likely that a significant fraction of the epilepsy genome will be determined to exert a predominant impact on inhibitory processes. In a major form of childhood epilepsy (absence epilepsy), essentially all known genes are ion channels involved in phasic and tonic inhibition in the thalamocortical circuit 62 .…”

Section: Defining Major and Branch Pathways: Lessons From Cancermentioning

confidence: 99%

Pathway-driven discovery of epilepsy genes

2015

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Epilepsy genes deliver critical insights into the molecular control of brain synchronization and are revolutionizing our understanding and treatment of the disease. The epilepsy-associated genome is rapidly expanding, and two powerful complementary approaches, isolation of de novo exome variants in patients and targeted mutagenesis in model systems, account for the steep increase. In sheer number, the tally of genes linked to seizures will likely match that of cancer and exceed it in biological diversity. The proteins act within most intracellular compartments and span the molecular determinants of firing and wiring in the developing brain. Every facet of neurotransmission, from dendritic spine to exocytotic machinery, is in play, and defects of synaptic inhibition are over-represented. The contributions of somatic mutations and noncoding microRNAs are also being explored. The functional spectrum of established epilepsy genes and the arrival of rapid, precise technologies for genome editing now provide a robust scaffold to prioritize hypothesis-driven discovery and further populate this genetic proto-map. Although each gene identified offers translational potential to stratify patient care, the complexity of individual variation and covert actions of genetic modifiers may confound single-gene solutions for the clinical disorder. In vivo genetic deconstruction of epileptic networks, ex vivo validation of variant profiles in patient-derived induced pluripotent stem cells, in silico variant modeling and modifier gene discovery, now in their earliest stages, will help clarify individual patterns. Because seizures stand at the crossroads of all neuronal synchronization disorders in the developing and aging brain, the neurobiological analysis of epilepsy-associated genes provides an extraordinary gateway to new insights into higher cortical function.

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Monogenic models of absence epilepsy

Cited by 65 publications

References 128 publications

Stxbp1/Munc18-1 haploinsufficiency in mice recapitulates key features of STXBP1 encephalopathy and impairs cortical inhibition

Stxbp1/Munc18-1 haploinsufficiency in mice recapitulates key features of STXBP1 encephalopathy and impairs cortical inhibition

Tapping the Brakes: Cellular and Synaptic Mechanisms that Regulate Thalamic Oscillations

Pathway-driven discovery of epilepsy genes

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