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Channelrhodopsins are light-gated ion channels used to control excitability of designated cells in large networks with high spatiotemporal resolution. While ChRs selective for H + , Na + , K + and anions have been discovered or engineered, Ca 2+ -selective ChRs have not been reported to date. Here, we analyse ChRs and mutant derivatives with regard to their Ca 2+ permeability and improve their Ca 2+ affinity by targeted mutagenesis at the central selectivity filter. The engineered channels, termed CapChR1 and CapChR2 for ca lcium- p ermeable ch annel r hodopsins, exhibit reduced sodium and proton conductance in connection with strongly improved Ca 2+ permeation at negative voltage and low extracellular Ca 2+ concentrations. In cultured cells and neurons, CapChR2 reliably increases intracellular Ca 2+ concentrations. Moreover, CapChR2 can robustly trigger Ca 2+ signalling in hippocampal neurons. When expressed together with genetically encoded Ca 2+ indicators in Drosophila melanogaster mushroom body output neurons, CapChRs mediate light-evoked Ca 2+ entry in brain explants. To date, no Ca2 + -selective channelrhodopsins have been characterized. In this study, Fernandez Lahore et al. report two calcium-permeable channelrhodopsins (CapChR1 and 2) for the photocontrol of calcium signalling in excitable tissue.

Epilepsy represents a significant medical challenge, with a third of patients failing to achieve seizure freedom despite the use of multiple different anti‐seizure medications (ASM). Drug resistance is common in genetically caused epilepsies. Patients are faced with repeated, long‐lasting, and frequently frustrating drug testing, necessitating targeted therapies and drug repurposing. While in silico tools offer some insight, novel and often genetic epilepsies require preclinical models, which are expensive and time‐consuming. Here, we propose Drosophila melanogaster as a rapid in vivo model for preclinical ASM efficacy testing using the sodium channel‐associated epilepsies, Dravet syndrome (DS), and generalized epilepsy with febrile seizures plus (GEFS+) as model disorders. We utilize vinegar fly models of DS and GEFS+ that exhibit phenotypic similarities to human patients, including seizures and increased morbidity. Moreover, treatment with ASM effective in humans (clobazam, stiripentol, fenfluramine) reduces seizures, while the application of sodium channel blocking ASM (phenytoin) was deleterious, underlining the model's utility. The utilization of Drosophila as a preclinical model offers a promising avenue for studying genetic epilepsies and assessing ASM efficacy. This approach has the potential to facilitate the development of tailored treatments for patients using a rapidly available in vivo model. Plain Language Summary Epilepsy is a challenging condition, with about one‐third of patients unable to control seizures despite trying multiple drug treatments. This is especially common in genetic epilepsies. Developing new treatments is expensive and slow, highlighting the need for faster, targeted approaches. This study uses the fly (Drosophila melanogaster) as a rapid, cost‐effective model to study genetic epilepsies like Dravet syndrome (DS). These fly models mimic key symptoms seen in humans, including seizures and shorter lifespans. Effective human anti‐seizure medications (e.g., clobazam, stiripentol, and fenfluramine) reduced seizures, while sodium channel blockers like phenytoin worsened them. The Drosophila model offers a promising and efficient way to study genetic epilepsies and test treatments, accelerating the development of more targeted therapies.

In vertebrates, several forms of memory-relevant synaptic plasticity involve postsynaptic rearrangements of glutamate receptors. In contrast, previous work indicates that Drosophila and other invertebrates store memories using presynaptic plasticity of cholinergic synapses. Here, we provide evidence for postsynaptic plasticity at cholinergic output synapses from the Drosophila mushroom bodies (MBs). We find that the nicotinic acetylcholine receptor (nAChR) subunit α5 is required within specific MB output neurons for appetitive memory induction but is dispensable for aversive memories. In addition, nAChR α2 subunits mediate memory expression and likely function downstream of α5 and the postsynaptic scaffold protein discs large (Dlg). We show that postsynaptic plasticity traces can be induced independently of the presynapse, and that in vivo dynamics of α2 nAChR subunits are changed both in the context of associative and non-associative (familiarity) memory formation, underlying different plasticity rules. Therefore, regardless of neurotransmitter identity, key principles of postsynaptic plasticity support memory storage across phyla.

It was classically suggested that behaviour can cause emotions (Darwin 1872). For example, smiling can make us feel happier, and in rodents the induced patterns of cardiac activity and breathing that are indicative of fear can in turn evoke it (Coles et al. 2022, Hsueh et al. 2023, Jhang et al. 2024). However, the adaptive significance of such feedback is unclear. We show that inducing backward movement, an element of avoidance behaviour in , engages negative valence signals in these animals, and reveal the neuronal mechanisms and adaptive significance of this effect. We develop a paradigm with odours as conditioned stimuli paired with optogenetically induced backward movement instead of a punishing unconditioned stimulus, and combined these experiments with pharmacology, high-resolution video tracking, functional imaging, connectome analyses, and modelling. Our results show that backward movement engages dopaminergic punishment neurons and supports aversive memories. Such avoidance-to-punishment feedback counterbalances extinction learning and maintains learned avoidance, reducing the risk of further punishment. This can explain the long-standing \"avoidance paradox\", the observation that avoidance adaptively persists even when it is successful and no punishment is received (Bolles 1972). Our results provide a neurobiologically grounded argument for an integrated view of behaviour organization and valence processing.