Most insects, including agricultural pests and disease vectors, rely on olfaction for key innate behaviors. Consequently, there is growing interest in studying insect olfaction to gain insights into odor-driven behavior and to support efforts in vector control. Calcium imaging using GCaMP fluorescence is widely used to identify olfactory receptor neurons (ORNs) responsive to ethologically relevant odors. However, accurate interpretation of GCaMP signals in the antenna requires understanding both response uniformity within an ORN population and how calcium signals relate to spike activity. To address this, we optimized a dual-modality recording method combining single-sensillum electrophysiology and widefield imaging for Drosophila ORNs. Calcium imaging showed that homotypic ab2A neurons exhibit similar odor sensitivity, consistent with spike recordings, indicating that a single ORN’s response can reliably represent its homotypic counterparts. Furthermore, concurrent dual recordings revealed that peak calcium responses are linearly correlated with spike activity, regardless of imaging site (soma or dendrites), GCaMP variant, odorant, or fly age. These findings validate the use of somatic calcium signals as a reliable proxy for spike activity in fly ORNs and provide a foundation for future large-scale surveys of spike–calcium response relationships across diverse ORN types.

Previous studies have reported associations between risk of Alzheimer’s disease (AD) or dementia and rare coding variants in a number of genes. A two-stage strategy was used in which a previously released whole exome sequenced sample was used to prioritise 100 genes showing the strongest evidence for association with AD. These genes were then analysed in a newly released whole genome sequenced sample to identify those which showed statistically significant evidence for rare coding variant association. Association analysis of loss of function (LOF) and nonsynonymous variants was carried out in 18,998 protein-coding genes using 11,188 controls and 5,808 cases, with nonsynonymous variants being annotated using 45 different pathogenicity predictors. The 100 genes showing strongest evidence for association were then analysed in a new sample of 27,749 controls and 13,234 cases using only the pathogenicity predictor which had performed best in the first sample. Four genes were statistically significant after correction for multiple testing: ABCA7, PSEN1, SORL1 and TREM2. The association of different categories of variant with AD was characterised and the pattern was seen to vary between genes. This study quantifies the contribution of different types of variant within each gene to AD risk. In general, these variants are probably too rare to be clinically useful for assessing individual risk of AD. Further research into the mechanisms whereby the products of these genes affect AD pathogenesis may aid development of novel therapeutic strategies.

Ribonucleoprotein granules (mRNP granules) are thought to contribute to the control of neuronal mRNA translation required for consolidation of long-term memories. Consistent with this, the function of Ataxin-2 in mRNA granule assembly has been shown to be required for long-term olfactory habituation (LTH) in Drosophila, a form of non-associative memory. Knockdown of Ataxin-2 in either local interneurons (LNs) or projection neurons (PNs) of the insect antennal lobe disrupts LTH while leaving short-term habituation intact, leading to a model in which Ataxin-dependent translational control is required in both presynaptic and postsynaptic elements of the LN-PN synapse, whose potentiation has been causally linked to LTH. Here we use novel and established methods for cell-type specific perturbation to ask: (a) whether Ataxin-2 controls mRNA granule assembly in cell types beyond the few that have been examined; and (b) whether it functions not only in LTH, but also for long-term olfactory associative memory (LTM). We show that Ataxin-2 controls mRNP granule assembly in additional neuronal types, namely Kenyon Cells (KCs) that encode associative memory, as well as more broadly in non-neuronal cells, e.g. in nurse cells in the egg chamber. Furthermore, selective knockdown of Atx2 in α/β and α’/β’ KCs blocks appetitive long-term but not short-term associative memories. Taken together these observations support a hypothesis that Ataxin-2 dependent translational control is widely required across different mnemonic circuits for consolidation of respective forms of long-term memories.

Forgetting behavior is a common phenomenon that has been widely studied in various model organisms, including Caenorhabditis elegans (C. elegans), Drosophila, and mammals such as mice and humans. Understanding the mechanisms underlying forgetting can provide valuable insights into potential treatments for memory-related disorders. In this study, C. elegans was used as a model organism to establish a forgetting model based on the PA14 pathogen. A proteomic analysis of signaling pathways involved in forgetting revealed the role of the Arp2/3 complex in regulating pathogen-induced forgetting. Manipulation of genes encoding the components of the Arp2/3 complex (arx-1, arx-2, arx-3, arx-5, and arx-7) led to a reduction in the duration of pathogen-induced forgetting. Additionally, one hour after pathogen removal, a significant decrease in the mRNA levels of arx-5 and arx-7 was observed, along with a reduction in arx-2::mCherry fluorescence in specific tissues of C. elegans. This study demonstrates that C. elegans exhibits forgetting behavior towards PA14, with a forgetting duration of approximately 2 hours. Pathogen-induced forgetting is associated with an increase in heterogeneous proteins localized to the cytoskeleton. Moreover, the expression levels of genes related to the Arp2/3 complex (arx-1, arx-2, arx-3, arx-5, and arx-7) are reduced, inhibiting cytoskeleton nucleation in cells. This inhibition may contribute to the observed pathogen-induced forgetting in C. elegans in response to PA14.

The swift updates of public databases and advancements in next-generation sequencing (NGS) technologies have enhanced the genetic identification capacities of epilepsy clinics. This study aimed to evaluate the diagnostic efficacy of NGS in pediatric epilepsy patients as a whole and to present the data obtained in the whole exome sequence analysis. We enrolled 40 children with suspected childhood epilepsy in this study. All patients underwent evaluation by a clinical geneticist or pediatric neurologist and the molecular genetic analysis of those children was performed by whole-exome sequencing (WES). Out of the 40 patients, 12 (30%) received a genetic diagnosis, involving 14 mutations across 13 genes. The cumulative positive diagnostic yield was 30%. Twelve of these patients were identified to have 5 variants previously documented as pathogenic, 9 variants classified as likely pathogenic, and 5 novel variants that have not been reported before. The outcomes indicate that whole-exome sequencing offers great benefits in clinical patient diagnosis, particularly in terms of detecting diagnostic variants. This study underscored the significance of whole exome sequencing (WES) studies, where only a broad gene set is examined in epilepsy patients. This approach has the potential to establish gene-specific phenotypic profiles, particularly by uncovering novel candidate genes in epilepsy patients with well-defined phenotypes. Additionally, conducting validation studies on variants of uncertain clinical significance could enhance the outcome yield.

The neurogenetics and vision community recently mourned William L. Pak, PhD, whose pioneering work spearheaded the genetic, electrophysiological, and molecular bases of biological processes underpinning vision. This essay provides a historical background to the daunting challenges and personal experiences that carved the path to seminal findings. It also reflects on the intellectual framework, mentoring philosophy, and inspirational legacy of Bill Pak's research. An emphasis and perspectives are placed on the discoveries and implications to date of the phosphatidylinositol-specific phospholipase C (PI-PLC), NorpA, and the cyclophilin, NinaA of the fruit fly, Drosophila melanogaster, and their respective mammalian homologues, PI-PLCβ4, and cyclophilin-related protein, Ran-binding protein 2 (Ranbp2) in critical biological processes and diseases of photoreceptors and other neurons.

Glutathione S-transferase omega (GSTO) is an antioxidant enzyme involved in reducing oxidative stress. Recent studies suggest that polymorphic variants of GSTOs affect the onset age and progression of neurodegenerative diseases. Although GSTO activity may affect the development and age dependency of several diseases, the mechanism by which GSTO inactivation in neurons regulates the susceptibility to neurodegenerative diseases is unclear. In the present study, GstO2 knockdown in Drosophila led to increased levels of Cabeza (Caz) protein in neurons in an age-dependent manner. Drosophila Caz is the ortholog of human FUS, which is associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that cytoplasmic Caz mislocalization and aggregation in neurons significantly increased after GstO2 knockdown in vivo. Downregulation of GstO2 decreased the solubility of the Caz protein in aging neurons. These findings demonstrate that GSTO is a critical modulator of the development of neurodegenerative diseases by regulating Caz localization and aggregation in the nervous system of Drosophila.