The effect of pharmacological inhibition of Serine Proteases on neuronal networks in vitro

This work was supported by the European Union\u2019s Framework Programme for Research and Innovation (under the H2020 ETN grant n. 642881 to Stefanie Dedeurwaerdere, Pieter Van Der Veken, and Koen Augustyns; under the Specific Grant Agreement n. 785907 - Human Brain Project to Michele Giugliano; and under FP7 grants n. 286403 and n. 284801 to Michele Giugliano), the European Union\u2019s Research Area Networks (NEURON II to Stefanie Dedeurwaerdere), the Flemish Research Foundation (grants n. G0F1517N and n. K201619N to Michele Giugliano), the University of Antwerp (grant n. BOF-DOCPRO-2016 to Michele Giugliano), and the Scuola Internazionale Superiore di Studi Avanzati (\u2018\u2018Collaborazione di Eccellenza 2018\u2019\u2019 to Michele Giugliano). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Identification of gene regulatory networks affected across drug-resistant epilepsies

Epilepsy is a chronic and heterogenous disease characterized by recurrent unprovoked seizures, that are commonly resistant to antiseizure medications. This study applies a transcriptome network-based approach across epilepsies aiming to improve understanding of molecular disease pathobiology, recognize affected biological mechanisms and apply causal reasoning to identify therapeutic hypotheses. This study included the most common drug-resistant epilepsies (DREs), such as temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), and mTOR pathway-related malformations of cortical development (mTORopathies). This systematic comparison characterized the global molecular signature of epilepsies, elucidating the key underlying mechanisms of disease pathology including neurotransmission and synaptic plasticity, brain extracellular matrix and energy metabolism. In addition, specific dysregulations in neuroinflammation and oligodendrocyte function were observed in TLE-HS and mTORopathies, respectively. The aforementioned mechanisms are proposed as molecular hallmarks of DRE with the identified upstream regulators offering opportunities for drug-target discovery and development

Astroglial calcium signaling and homeostasis in tuberous sclerosis complex

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors in various organs, including the brain, and is often accompanied by epilepsy, neurodevelopmental comorbidities including intellectual disability and autism. A key hallmark of TSC is the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, which induces alterations in cortical development and metabolic processes in astrocytes, among other cellular functions. These changes could modulate seizure susceptibility, contributing to the progression of epilepsy and its associated comorbidities. Epilepsy is characterized by dysregulation of calcium (Ca 2+) channels and intracellular Ca 2+ dynamics. These factors contribute to hyperexcitability, disrupted synaptogenesis, and altered synchronization of neuronal networks, all of which contribute to seizure activity. This study investigates the intricate interplay between altered Ca 2+ dynamics, mTOR pathway dysregulation, and cellular metabolism in astrocytes. The transcriptional profile of TSC patients revealed significant alterations in pathways associated with cellular respiration, ER and mitochondria, and Ca 2+ regulation. TSC astrocytes exhibited lack of responsiveness to various stimuli, compromised oxygen consumption rate and reserve respiratory capacity underscoring their reduced capacity to react to environmental changes or cellular stress. Furthermore, our study revealed significant reduction of store operated calcium entry (SOCE) along with strong decrease of basal mitochondrial Ca 2+ concentration and Ca 2+ influx in TSC astrocytes. In addition, we observed alteration in mitochondrial membrane potential, characterized by increased depolarization in TSC astrocytes. Lastly, we provide initial evidence of structural abnormalities in mitochondria within TSC patient-derived astrocytes, suggesting a potential link between disrupted Ca 2+ signaling and mitochondrial dysfunction. Our findings underscore the complexity of the relationship between Ca 2+ signaling, mitochondria dynamics, apoptosis, and mTOR hyperactivation. Further exploration is required to shed light on the pathophysiology of TSC and on TSC associated neuropsychiatric disorders offering further potential avenues for therapeutic development