Neuroinflammation: A Signature or a Cause of Epilepsy?

Epilepsy can be both a primary pathology and a secondary effect of many neurological conditions. Many papers show that neuroinflammation is a product of epilepsy, and that in pathological conditions characterized by neuroinflammation, there is a higher probability to develop epilepsy. However, the bidirectional mechanism of the reciprocal interaction between epilepsy and neuroinflammation remains to be fully understood. Here, we attempt to explore and discuss the relationship between epilepsy and inflammation in some paradigmatic neurological and systemic disorders associated with epilepsy. In particular, we have chosen one representative form of epilepsy for each one of its actual known etiologies. A better understanding of the mechanistic link between neuroinflammation and epilepsy would be important to improve subject-based therapies, both for prophylaxis and for the treatment of epilepsy.

Perturbation of Cortical Excitability in a Conditional Model of PCDH19 Disorder.

PCDH19 epilepsy (DEE9) is an X-linked syndrome associated with cognitive and behavioral disturbances. Since heterozygous females are affected, while mutant males are spared, it is likely that DEE9 pathogenesis is related to disturbed cell-to-cell communication associated with mosaicism. However, the effects of mosaic PCDH19 expression on cortical networks are unknown. We mimicked the pathology of DEE9 by introducing a patch of mosaic protein expression in one hemisphere of the cortex of conditional PCDH19 knockout mice one day after birth. In the contralateral area, PCDH19 expression was unaffected, thus providing an internal control. In this model, we characterized the physiology of the disrupted network using local field recordings and two photon Ca2+ imaging in urethane anesthetized mice. We found transient episodes of hyperexcitability in the form of brief hypersynchronous spikes or bursts of field potential oscillations in the 9-25 Hz range. Furthermore, we observed a strong disruption of slow wave activity, a crucial component of NREM sleep. This phenotype was present also when PCDH19 loss occurred in adult mice, demonstrating that PCDH19 exerts a function on cortical circuitry outside of early development. Our results indicate that a focal mosaic mutation of PCDH19 disrupts cortical networks and broaden our understanding of DEE9.

Enhancing reproducibility in developmental EEG research: BIDS, cluster-based permutation tests, and effect sizes.

Developmental research using electroencephalography (EEG) offers valuable insights in brain processes early in life, but at the same time, applying this sensitive technique to young children who are often non-compliant and have short attention spans comes with practical limitations. It is thus of particular importance to optimally use the limited resources to advance our understanding of development through reproducible and replicable research practices. Here, we describe methodological approaches that help maximize the reproducibility of developmental EEG research. We discuss how to transform EEG data into the standardized Brain Imaging Data Structure (BIDS) which organizes data according to the FAIR data sharing principles. We provide a tutorial on how to use cluster-based permutation testing to analyze developmental EEG data. This versatile test statistic solves the multiple comparison problem omnipresent in EEG analysis and thereby substantially decreases the risk of reporting false discoveries. Finally, we describe how to quantify effect sizes, in particular of cluster-based permutation results. Reporting effect sizes conveys a finding's impact and robustness which in turn informs future research. To demonstrate these methodological approaches to data organization, analysis and report, we use a publicly accessible infant EEG dataset and provide a complete copy of the analysis code.

Perineuronal nets control visual input via thalamic recruitment of cortical PV interneurons.

In the neocortex, critical periods (CPs) of plasticity are closed following the accumulation of perineuronal nets (PNNs) around parvalbumin (PV)-positive inhibitory interneurons. However, how PNNs tune cortical function and plasticity is unknown. We found that PNNs modulated the gain of visual responses and γ-oscillations in the adult mouse visual cortex in vivo, consistent with increased interneuron function. Removal of PNNs in adult V1 did not affect GABAergic neurotransmission from PV cells, nor neuronal excitability in layer 4. Importantly, PNN degradation coupled to sensory input potentiated glutamatergic thalamic synapses selectively onto PV cells. In the absence of PNNs, increased thalamic PV-cell recruitment modulated feed-forward inhibition differently on PV cells and pyramidal neurons. These effects depended on visual input, as they were strongly attenuated by monocular deprivation in PNN-depleted adult mice. Thus, PNNs control visual processing and plasticity by selectively setting the strength of thalamic recruitment of PV cells.