Biology subjects

Cirelli, C.

Publications and source records attributed to Cirelli, C..

3 recordsLinked to original sources

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↗

bioRxiv2017

Role of somatostatin-positive cortical interneurons in the generation of sleep slow waves

Cortical slow waves - the hallmark of NREM sleep - reflect near-synchronous OFF periods in cortical neurons. However, the mechanisms triggering such OFF periods are unclear, as there is little evidence for somatic inhibition. We studied cortical inhibitory interneurons that express somatostatin (SOM), because [~]70% of them are Martinotti cells that target diffusely layer 1 and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation triggers neuronal OFF periods during sleep. Next, we show that chemogenetic activation of SOM+ cells increases slow wave activity (SWA), the slope of individual slow waves, and the duration of NREM sleep; whereas their chemogenetic inhibition decreases SWA and slow wave incidence without changing time spent asleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing. These results indicate that SOM+ cells, but not PV+ cells, are involved in the generation of sleep slow waves. Whether Martinotti cells are solely responsible for this effect, or are complemented by other classes of inhibitory neurons, remains to be investigated.

neuroscience↗