Biology subjects

Petrou, S.

Publications and source records attributed to Petrou, S..

3 recordsLinked to original sources

bioRxiv2017

Abnormal cell sorting underlies the unique X-linked inheritance of PCDH19 Epilepsy

X-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, Protocadherin 19 (PCDH19) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to highly specific combinatorial adhesion codes such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between WT PCDH19- and null PCDH19-expressing cells in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining specific adhesion codes during cortical development and how disruption of these codes is associated with the unique X-linked inheritance of PCDH19 epilepsy.

developmental biology↗

bioRxiv2017

Cortical Tonic Inhibition Regulates the Expression of Spike-and-Wave Discharges Associated with Absence Epilepsy.

Synchronous and bilateral spike-and-wave discharges accompany nonconvulsive behavioral and cognitive arrest during seizures associated with absence epilepsy. Previous investigation of multiple absence animal models suggests that the underlying cause of absence seizures is an increase in thalamic inhibitory tonic currents. In contrast, in this study we provide evidence that the level of cortical tonic inhibition also regulates absence seizure expression. Using continuous video-EEG recordings to monitor absence seizures and spike-and-wave discharge expression we show that pharmacological blockade of cortical tonic inhibition provokes absence seizures in wild-type mice. Furthermore, we show that pharmacological rescue of cortical tonic inhibition in an absence mouse ({gamma}2R43Q) model, which lacks tonic inhibition, suppresses absence seizure and spike-and-wave discharge expression. Collectively, these results suggest an optimum level of tonic inhibition in the thalamocortical circuit is required for normal functioning and that a deviation from this optimum results in aberrant thalamocortical function, SWDs and absence seizures.

neuroscience↗

bioRxiv2017

Tonic Inhibition is Abolished in GABAA Receptor γ2R43Q Knock-in Mice with Absence Epilepsy and Febrile Seizures.

The {gamma}2R43Q GABAA receptor mutation confers absence epilepsy in humans, and {gamma}2R43Q knock-in mice (RQ) display absence seizures and generalized spike-and-wave discharges reminiscent of their human counterparts. Previous work on several rodent models led to the conclusion that elevated tonic inhibition in thalamic neurons is necessary and sufficient to produce typical absence epilepsy. In contrast, here we used patch-clamp electrophysiology in brain slices to show that RQ mice entirely lack tonic inhibition in principal cells of layer II/III somatosensory cortex and ventrobasal thalamus. Additionally, protein quantification and multielectrode electrophysiology show that the mutation interferes with trafficking of GABAA receptor subunits involved in generating tonic currents, leading to increased cortical firing and decreased thalamic bursting rates. Together with previous work, our results suggest that an optimum level of tonic inhibition is required for normal thalamocortical function, such that deviations in either direction away from this optimum enhance susceptibility to absence seizures.

neuroscience↗