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BackgroundAngelman Syndrome (AS) is a rare neurodevelopmental disorder for which there is currently no cure or effective therapeutic. Since the genetic cause of AS is known to be dysfunctional expression of the maternal allele of ubiquitin protein ligase E3A (UBE3A), several genetic animal models of AS have been developed. Both the Ube3a maternal deletion mouse and rat models of AS reliably demonstrate behavioral phenotypes of relevance to AS and therefore offer suitable in vivo systems in which to test potential therapeutics. One promising candidate treatment is insulin-like growth factor-2 (IGF-2), which has recently been shown to ameliorate behavioral deficits in the mouse model of AS and improve cognitive abilities across model systems.MethodsWe used both the Ube3a maternal deletion mouse and rat models of AS to evaluate the ability of IGF-2 to improve electrophysiological and behavioral outcomes.ResultsAcute systemic administration of IGF-2 had an effect on electrophysiological activity in the brain and on a metric of motor ability; however the effects were not enduring or extensive. Additional metrics of motor behavior, learning, ambulation, and coordination were unaffected and IGF-2 did not improve social communication, seizure threshold, or cognition.LimitationsThe generalizability of these results to humans is difficult to predict and it remains possible that dosing schemes (i.e., chronic or subchronic dosing), routes, and/or post-treatment intervals other than that used herein may show more efficacy.ConclusionsDespite a few observed effects of IGF-2, our results taken together indicate that IGF-2 treatment does not profoundly improve behavioral deficits in mouse or rat models of AS. These findings shed cautionary light on the potential utility of acute systemic IGF-2 administration in the treatment of AS.

Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults. [ABSTRACT FROM AUTHOR]

Objective: Cardiac alterations represent a potential epilepsy‐associated comorbidity. Whether cardiac changes occur as a function of epilepsy duration is not well understood. We sought to evaluate whether cardiac alterations represented a time‐dependent phenomenon in pediatric epilepsy. Methods: We retrospectively followed pediatric epilepsy patients without preexisting cardiac conditions or ion channelopathies who had history of pediatric intensive care unit admission for convulsive seizures or status epilepticus between 4/2014 and 7/2017. All available 12‐lead electrocardiograms (ECGs) from these patients between 1/2006 and 5/2019 were included. We examined ECG studies for changes in rhythm; PR, QRS, or corrected QT intervals; QRS axis or morphology; ST segment; or T wave. Data were analyzed using multivariable models containing covariates associated with ECG changes or epilepsy duration from the univariate analyses. Results: 127 children with 323 ECGs were included in the analyses. The median epilepsy duration was 3.9 years (IQR 1.3‐8.4 years) at the time of an ECG study and a median of 2 ECGs (IQR 1‐3) per subject. The clinical encounters associated with ECGs ranged from well‐child visits to status epilepticus. We observed changes in 171 ECGs (53%), with 83 children (65%) had at least 1 ECG with alterations. In a multivariable logistic regression model adjusting for potentially confounding variables and accounting for clustering by patient, epilepsy duration was independently associated with altered ECGs for each year of epilepsy (OR: 1.1, 95% CI: 1.0‐1.2, P =.002). Extrapolating from this model, children with epilepsy durations of 10 and 15 years had 2.9 and 4.9 times the odds of having ECG changes, respectively. Significance: Cardiac alterations may become more common with increasing epilepsy duration in select pediatric epilepsy patients. Future studies are needed to determine the potential clinical implications and the generalizability of these observations. [ABSTRACT FROM AUTHOR]

Expression of immediate early genes (IEGs) in the brain is important for synaptic plasticity, and probably also in neurodegenerative conditions. To understand the cellular mechanisms of the underlying neuropathophysiological processes in epilepsy, we need to pinpoint changes in concentration of synaptic plasticity-related proteins at subsynaptic levels. In this study, we examined changes in synaptic expression of Activity-regulated cytoskeleton-associated (Arc) and Brai Derived Neurotrophic Factor (BDNF) in a rat model of kainate-induced temporal lobe epilepsy (TLE). Western blotting showed reduced concentrations of Arc and increased concentrations of BDNF in hippocampal synaptosomes in chronic TLE rats. Then, using quantitative electron microscopy, we found corresponding changes in subsynaptic regions in the hippocampus. Specifically, we detected significant reductions in the concentrations of Arc in the presynaptic terminal of Schaffer collateral glutamatergic synapses in the stratum radiatum of the CA1 area in TLE, as well as in their adjacent postsynaptic spines. In CA3, there was a significant reduction of Arc only in the presynaptic terminal cytoplasm. Conversely, in CA3, there was a significant increase in the expression of BDNF in the presynaptic terminal, but not in the postsynaptic spine. Significant increase in BDNF concentration in the CA1 postsynaptic density was also obtained. We hypothesize that the observed changes in Arc and BDNF may contribute to both cognitive impairment and increased excitotoxic vulnerability in chronic epilepsy. • Expression of Arc is reduced in hippocampal Schaffer collateral glutamatergic synapses in temporal lobe epilepsy. • The concentration of BDNF is increased in hippocampal Schaffer collateral glutamatergic synapses in temporal lobe epilepsy. • Synaptic changes in Arc and BDNF may contribute to increased excitotoxicity and cognitive impairments in chronic epilepsy. [ABSTRACT FROM AUTHOR]

Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)