Speaker
Description
Neurological disorders are highly prevalent (3 billion people around the globe are suffering from it), and due to the challenges associated with studying these pathologies in humans, the importance of in vitro human models is growing. The use of in vitro human models provides a more accurate representation of human biology, thereby enhancing our understanding of neurological disorders and the development of therapeutic interventions. Our group is focused on the generation of 2D and 3D human model.
2D human brain models. Building on a recently optimized protocol for differentiating iPSCs into glutamatergic neurons (iGluNeurons; Servetti et al., 2025), we generated iGluNeurons from iPSCs derived from patients affected by paroxysmal disorders caused by mutations in PRRT2 and SYN1. At the molecular level, PRRT2 influences sodium channel activity, playing a key role in regulating neuronal excitability, while SYN1 is involved in synaptic vesicle trafficking and neurotransmitter release at the presynaptic terminal. Mutations in these genes are associated with paroxysmal kinesigenic dyskinesia and infantile epilepsy (PRRT2) and focal seizures triggered by water contact (SYN1). iGluNeurons carrying PRRT2 mutations exhibited hyperexcitability, which we successfully rescued by applying subunit-specific sodium channel blockers. Meanwhile, iGluNeurons carrying SYN1 mutations are currently being characterized, with a focus on maturation and developmental differences.
3D human brain models. We have developed a novel Long-Term Air-Liquid Interface Culture protocol for generating hippocampal organoids and establishing recordings on HD-MEA, starting from DIV60 up to DIV180. Our results demonstrate that hippocampal organoids lack a necrotic core and exhibit functional, highly organized neural networks. Furthermore, we successfully integrated microglia into the hippocampal organoids. Notably, we observed a decrease in neuronal activity, which aligns with findings in mouse models of microglial deficiency, where an increase in activity has been reported.
These models could provide insights into pathophysiological mechanisms in human context and potential treatments.
| Author(s) | Martina Servetti*1,2, Martino Caramia1, Giulia Parodi3, Anna Corradi2,4, Fabio Benfenati1,4, Bruno Sterlini2,4 |
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| Affiliation(s) | "1 Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132, Genova, Italy. 2 Dipartimento di Medicina Sperimentale, Università di Genova, Viale Benedetto XV, 3, Genova, 16132, Italy. 3 Department of Informatics, Bioengineering, Robotics, and Systems Engineering (DIBRIS), University of Genova, Genoa, Italy. 4 IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, Genova, 16132, Italy." |
