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Inhibitory interneurons regulate cortical circuit activity, and their dysfunction has been implicated in autism spectrum disorder (ASD). 16p11.2 microdeletions are genetically linked to 1% of ASD cases. However, few studies investigate the effects of this microdeletion on interneuron development. Using ventral telencephalic organoids derived from human induced pluripotent stem cells, we have investigated the effect of this microdeletion on organoid size, progenitor proliferation and organisation into neural rosettes, ganglionic eminence marker expression at early developmental timepoints, and expression of the neuronal marker NEUN at later stages. At early stages, deletion organoids exhibited greater variations in size with concomitant increases in relative neural rosette area and the expression of the ventral telencephalic marker COUPTFII, with increased variability in these properties. Cell cycle analysis revealed an increase in total cell cycle length caused primarily by an elongated G1 phase, the duration of which also varied more than normal. At later stages, deletion organoids increased their NEUN expression. We propose that 16p11.2 microdeletions increase developmental variability and may contribute to ASD aetiology by lengthening the cell cycle of ventral progenitors, promoting premature differentiation into interneurons., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Background: Autism spectrum condition or 'autism' is associated with numerous genetic risk factors including the polygenic 16p11.2 microdeletion. The balance between excitatory and inhibitory neurons in the cerebral cortex is hypothesised to be critical for the aetiology of autism making improved understanding of how risk factors impact on the development of these cells an important area of research. In the current study we aim to combine bioinformatics analysis of human foetal cerebral cortex gene expression data with anatomical and electrophysiological analysis of a 16p11.2 +/- rat model to investigate how genetic risk factors impact on inhibitory neuron development., Methods: We performed bioinformatics analysis of single cell transcriptomes from gestational week (GW) 8-26 human foetal prefrontal cortex and anatomical and electrophysiological analysis of 16p11.2 +/- rat cerebral cortex and hippocampus at post-natal day (P) 21., Results: We identified a subset of human interneurons (INs) first appearing at GW23 with enriched expression of a large fraction of risk factor transcripts including those expressed from the 16p11.2 locus. This suggests the hypothesis that these foetal INs are vulnerable to mutations causing autism. We investigated this in a rat model of the 16p11.2 microdeletion. We found no change in the numbers or position of either excitatory or inhibitory neurons in the somatosensory cortex or CA1 of 16p11.2 +/- rats but found that CA1 Sst INs were hyperexcitable with an enlarged axon initial segment, which was not the case for CA1 pyramidal cells., Limitations: The human foetal gene expression data was acquired from cerebral cortex between gestational week (GW) 8 to 26. We cannot draw inferences about potential vulnerabilities to genetic autism risk factors for cells not present in the developing cerebral cortex at these stages. The analysis 16p11.2 +/- rat phenotypes reported in the current study was restricted to 3-week old (P21) animals around the time of weaning and to a single interneuron cell-type while in human 16p11.2 microdeletion carriers symptoms likely involve multiple cell types and manifest in the first few years of life and on into adulthood., Conclusions: We have identified developing interneurons in human foetal cerebral cortex as potentially vulnerable to monogenic autism risk factors and the 16p11.2 microdeletion and report interneuron phenotypes in post-natal 16p11.2 +/- rats., (© 2022. The Author(s).)

Competing Interests: The authors declare no conflict of interest.

Pax6 is a well-known regulator of early neuroepithelial progenitor development. Its constitutive loss has a particularly strong effect on the developing prethalamus, causing it to become extremely hypoplastic. To overcome this difficulty in studying the long-term consequences of Pax6 loss for prethalamic development, we used conditional mutagenesis to delete Pax6 at the onset of neurogenesis and studied the developmental potential of the mutant prethalamic neurons in vitro. We found that Pax6 loss affected their rates of neurite elongation, the location and length of their axon initial segments, and their electrophysiological properties. Our results broaden our understanding of the long-term consequences of Pax6 deletion in the developing mouse forebrain, suggesting that it can have cell-autonomous effects on the structural and functional development of some neurons., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Background: Altering the natural flow regime, an essential component of healthy fluvial systems, through hydropower operations has the potential to negatively impact freshwater fish populations. Establishing improved management of flow regimes requires better understanding of how fish respond to altered flow components, such as flow magnitude. Based on the results of a recent systematic map on the impacts of flow regime changes on direct outcomes of freshwater or estuarine fish productivity, evidence clusters on fish abundance and biomass responses were identified for full systematic review. The primary goal of this systematic review is to address one of those evidence clusters, with the following research question: how do changes in flow magnitude due to hydropower operations affect fish abundance and biomass?, Methods: This review follows the guidelines of the Collaboration for Environmental Evidence. It examined commercially published and grey literature originally identified during the systematic map process and a systematic search update. All articles were screened using an a priori eligibility criteria at two stages (title and abstract, and full-text) and consistency checks were performed at all stages. All eligible articles were assessed for study validity and specifically designed data extraction and study validity tools were used. A narrative synthesis included all available evidence and meta-analysis using the standardized mean difference (Hedges' g) was conducted where appropriate., Review Findings: A total of 133 studies from 103 articles were included in this systematic review for data extraction and critical appraisal. Most studies were from North America (60%) and were conducted at 146 different hydropower dams/facilities. Meta-analysis included 268 datasets from 58 studies, separated into three analyses based on replication type [temporal (within or between year replication) or spatial]. Fish abundance (226 datasets) and biomass (30 datasets) had variable responses to changes in flow magnitude with estimated overall mean effect sizes ranging from positive to negative and varying by study design and taxa. In studies with temporal replication, we found a detectable effect of alterations to the direction of flow magnitude, the presence of other flow components, sampling methods, season, and fish life stage. However, we found no detectable effect of these moderators for studies with spatial replication. Taxonomic analyses indicated variable responses to changes in flow magnitude and a bias towards salmonid species., Conclusions: This synthesis did not find consistent patterns in fish abundance or biomass responses to alterations or changes in flow magnitude. Fish responses to flow magnitude alterations or changes were highly variable and context dependent. Our synthesis suggests that biotic responses may not be generalizable across systems impacted by hydroelectric power production and operations, where specific features of the system may be highly influential. Site-specific and adaptive management may be necessary. To improve study validity and interpretability, studies with long-term continuous monitoring, and both temporal and spatial replication are needed. When this gold standard is unfeasible, studies should strive, at minimum, to maximize replication within both intervention and comparator groups for either temporal or spatial designs. To further address knowledge gaps, studies are needed that focus on non-salmonids, multiple seasons, and systems outside of North America., (© 2022. The Author(s).)