GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility

Judson, Matthew C.; Wallace, Michael L.; Sidorov, Michael S.; Burette, A; Gu, Bin; Woerden, Geeske M M. van; King, Ian; Han, Ji Eun; Zylka, Mark J.; Elgersma, Ype; Weinberg, Richard J.; Philpot, Benjamin D.

doi:10.1016/j.neuron.2016.02.040

Cited by 137 publications

(157 citation statements)

References 72 publications

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“…These human syndromes and their corresponding mouse models are manifested in epilepsy, which affects GABAergic modulatory neurotransmission but lacks observed motor convulsions (36,64). Also, we noted expression changes concordant with systematic facilitation of cholinergic synaptic activation following Dox; specifically, this involved simultaneous elevation in the excitatory nicotinic receptors 5 and 7 and muscarinic receptor 5, and down-regulation of the inhibitory muscarinic receptors 2 and 4.…”

Section: Discussionsupporting

confidence: 56%

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

Bekenstein

Mishra

Milikovsky

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain micro-RNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergicmediated seizures by intersecting forebrain miR profiles that were Argonaute precipitated, synaptic vesicle target enriched, or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic antiinflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating miR-134. RNA sequencing demonstrated in doxycycline-treated dTg-211 cortices overrepresentation of synaptic activity, Ca 2+ transmembrane transport, TGFBR2 signaling, and cholinergic synapse pathways. Additionally, a cholinergic dysregulated mouse model overexpressing a miR refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases, and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hypersynchronization and nonconvulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and interference with epilepsy.

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Section: Discussionsupporting

confidence: 56%

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

Bekenstein

Mishra

Milikovsky

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Angelman syndrome, most commonly caused by maternal deletion of the 15q11-q13 region, including UBE3A , features enhanced delta oscillations in clinical EEG recordings [34, 35], suggesting a reciprocal relationship between deletion and duplication of the GABA A R subunits. Furthermore, loss of UBE3A has been associated with enhanced delta oscillations [36] and suppression of ventral striatal GABA co-release in mouse models of Angelman syndrome [37], underscoring the relationship between the ubiquitin ligase and GABAergic transmission.…”

Section: Discussionmentioning

confidence: 99%

A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome

Frohlich

Şentürk²,

Saravanapandian

et al. 2016

PLoS ONE

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BackgroundDuplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism spectrum disorder (ASD). A distinct electrophysiological (EEG) pattern characterized by excessive activity in the beta band has been noted in clinical reports. We asked whether EEG power in the beta band, as well as in other frequency bands, distinguished children with Dup15q syndrome from those with non-syndromic ASD and then examined the clinical correlates of this electrophysiological biomarker in Dup15q syndrome.MethodsIn the first study, we recorded spontaneous EEG from children with Dup15q syndrome (n = 11), age-and-IQ-matched children with ASD (n = 10) and age-matched typically developing (TD) children (n = 9) and computed relative power in 6 frequency bands for 9 regions of interest (ROIs). Group comparisons were made using a repeated measures analysis of variance. In the second study, we recorded spontaneous EEG from a larger cohort of individuals with Dup15q syndrome (n = 27) across two sites and examined age, epilepsy, and duplication type as predictors of beta power using simple linear regressions.ResultsIn the first study, spontaneous beta1 (12–20 Hz) and beta2 (20–30 Hz) power were significantly higher in Dup15q syndrome compared with both comparison groups, while delta (1–4 Hz) was significantly lower than both comparison groups. Effect sizes in all three frequency bands were large (|d| > 1). In the second study, we found that beta2 power was significantly related to epilepsy diagnosis in Dup15q syndrome.ConclusionsHere, we have identified an electrophysiological biomarker of Dup15q syndrome that may facilitate clinical stratification, treatment monitoring, and measurement of target engagement for future clinical trials. Future work will investigate the genetic and neural underpinnings of this electrophysiological signature as well as the functional consequences of excessive beta oscillations in Dup15q syndrome.

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“…The increased SK2 potassium channel levels for after-hyperpolarization in Ube3a m − /p + might suggest a decrease of excitability as well (Sun et al 2015). Interestingly, GABAergic neuron specific loss of Ube3a results in abnormal EEG and enhanced seizure susceptibility (Judson et al 2016; Santini and Klann 2016). …”

Section: Introductionmentioning

confidence: 99%

Lovastatin suppresses hyperexcitability and seizure in Angelman syndrome model

Chung

Bey

Towers

et al. 2018

Neurobiology of Disease

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Epilepsy is prevalent and often medically intractable in Angelman syndrome (AS). AS mouse model (Ube3am−/p+) shows reduced excitatory neurotransmission but lower seizure threshold. The neural mechanism linking the synaptic dysfunction to the seizure remains elusive. We show that the local circuits of Ube3am−/p+ in vitro are hyperexcitable and display a unique epileptiform activity, a phenomenon that is reminiscent of the finding in fragile X syndrome (FXS) mouse model. Similar to the FXS model, lovastatin suppressed the epileptiform activity and audiogenic seizures in Ube3am−/p+. The in vitro model of Ube3am−/p+ is valuable for dissection of neural mechanism and epilepsy drug screening in vivo.

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GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility

Cited by 137 publications

References 72 publications

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome

Lovastatin suppresses hyperexcitability and seizure in Angelman syndrome model

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