Challenges to ethical public engagement in research funding: a perspective from practice.

European research funding organizations (RFOs) are increasingly experimenting with public engagement in their funding activities. This case study draws attention to the challenges they face in preparing, implementing, and evaluating ethical public engagement in the context of setting funding priorities, formulating calls for proposals, and evaluating project proposals. We discuss challenges related to seven themes: (1) recruiting participants; (2) commitments and expectations; (3) meaningful dialogue and equal engagement; (4) accommodating vulnerability; (5) funding call formulations; (6) lack of expertise in engagement ethics; and (7) uncertainty, resource constraints, and external factors.

CACNA1A haploinsufficiency leads to reduced synaptic function and increased intrinsic excitability.

Haploinsufficiency of the CACNA1A gene, encoding the pore-forming α1 subunit of P/Q-type voltage-gated calcium channels, is associated with a clinically variable phenotype ranging from cerebellar ataxia, to neurodevelopmental syndromes with epilepsy and intellectual disability. To understand the pathological mechanisms of CACNA1A loss-of-function variants, we characterized a human neuronal model for CACNA1A haploinsufficiency, by differentiating isogenic induced pluripotent stem cell lines into glutamatergic neurons, and investigated the effect of CACNA1A haploinsufficiency on mature neuronal networks through a combination of electrophysiology, gene expression analysis, and in silico modeling. We observed an altered network synchronization in CACNA1A+/- networks alongside synaptic deficits, notably marked by an augmented contribution of GluA2-lacking AMPA receptors.

Breaking the burst: Unveiling mechanisms behind fragmented network bursts in patient-derived neurons.

Fragmented network bursts (NBs) are observed as a phenotypic driver in many patient-derived neuronal networks on multi-electrode arrays (MEAs), but the pathophysiological mechanisms underlying this phenomenon are unknown. Here, we used our previously developed biophysically detailed in silico model to investigate these mechanisms. Fragmentation of NBs in our model simulations occurred only when the level of short-term synaptic depression (STD) was enhanced, suggesting that STD is a key player.

Unraveling Dravet Syndrome: Exploring the complex effects of sodium channel mutations on neuronal networks.

Dravet Syndrome (DS) is a severe developmental epileptic encephalopathy with frequent intractable seizures accompanied by cognitive impairment, often caused by pathogenic variants in encoding sodium channel Na1.1. Recent research utilizing patient-derived neuronal networks and accompanying models uncovered that not just sodium-but also potassium-and synaptic currents were impaired in DS networks.

Degree of differentiation impacts neurobiological signature and resistance to hypoxia of SH-SY5Y cells.

SH-SY5Y cells are valuable neuronalmodels for studying patho-mechanisms and treatment targets in brain disorders due to their easy maintenance, rapid expansion, and low costs. However, the use of various degrees of differentiation hampers appreciation of results and may limit the translation of findings to neurons or the brain. Here, we studied the neurobiological signatures of SH-SY5Y cells in terms of morphology, expression of neuronal markers, and functionality at various degrees of differentiation, as well as their resistance to hypoxia.