Neuroscience

eLife assessment

This manuscript has a number of important findings in the interesting area of attempts to rescue neurodevelopmental phenotypes in the postnatal setting. Ameliorating some of the symptoms of Angelman syndrome at later stages is potentially of major clinical significance and this study provides support for that possibility. More generally, this study also shows that treatment of a syndrome like Angelman with antisense oligonucleotides to modulate allele-specific expression at later stages of life has potential.

eLife assessment

This manuscript presents a theory of generalization in neural population codes and proposes sample efficiency as a new normative principle distinct from efficient coding. The theory suggests that, with small numbers of training examples, generalization performance depends exclusively on the population code's 'kernel' (pairwise similarity between population activity patterns), and that sample-efficient learning depends on whether the task is aligned with the population's inductive bias (i.e., the top eigenfunctions of the kernel). The theory can be used to identify the set of 'easily learnable' stimulus-response mappings from neural data which makes strong behavioral predictions that can be easily evaluated.

eLife assessment

This manuscript provides a valuable resource for scientists who wish to manipulate second messengers in zebrafish using optogenetics. The authors provide solid evidence, based on behaviour, monitoring of heart beat and imaging, that several of the opsins tested can have an effect in larval fish. Opsins that lack an effect are also described. As the second messengers affected by the tools are found in multiple cell types, the results should be of interest of scientists working in a variety of areas.

eLife assessment

This work provides a potentially useful resource for scientists who wish to use optogenetics to manipulate GPCR signalling in larval zebrafish. It compares the physiological effects of different vertebrate and invertebrate rhodopsins expressed in either reticulospinal neurons or cardiomyocytes. The evidence for light-induced effects on behavior (either tail bending or heart beating) is solid, although only limited cell types and conditions are tested.

eLife assessment

This manuscript is of interest to neuroimaging scientists and neurophysiologists studying the glymphatic system. Using a multi-modal approach including magnetic resonance and histological methods, this work provides substantial data interrogating the effect of removing of aquaporin-4 (AQP4) from the mouse brain parenchyma on the structural morphology and interstitial fluid dynamics stagnation. In particular, the authors provide evidence that deletion of AQP4 in mice results in increased interstitial volume, likely due to increased resistance to parenchymal CSF efflux.

eLife assessment

This useful study highlights the contribution of the medial temporal lobe (MTL), and the DG/CA3 hippocampal pathway in particular, to neural activity during the working memory delay period. The evidence supporting this is compelling, using diverse state-of-the-art approaches to neural data analysis and relating it to behavioural data. The work will be of significant interest to neuroscientists specialising in the research area of human working memory.

eLife assessment

Using in-vivo proximity labeling using three different presynaptic proteins the authors have carried out a comprehensive proteome analysis of axonal dopamine release sites, resulting in the identification of many new presynaptic candidate proteins. Genetic deletion of the active zone protein RIM1 but not of the presynaptic calcium sensor synaptotagmin 1 resulted in a loss of enrichment indicative of a disruption of the active zone. Although the functional significance of many of the novel proteins will require future corroboration, the analysis provides a valuable and high-quality dataset as a starting point for future investigations.

eLife assessment

This study addresses a fundamental question about the spatiotemporal location of neurotransmitter release in a synapse with essential implications for postsynaptic signaling and neural excitability in general. The authors provide convincing evidence on non-overlapping nanometer scale organization of the two primary forms of evoked vesicle fusion (synchronous and asynchronous) in the synapse. They utilize tools for super-resolution assessment of synaptic transmission that were previously developed in their lab, in this way they help bridge earlier work based on imaging approaches that lack temporal resolution and electrophysiological results lacking spatial resolution.

eLife assessment

In this study, the authors provide important findings supporting a key role for TLP2 as a regulator of neurotoxic and pro-inflammatory cytokine and chemokine release following acute and chronic neuroinflammation. They provide convincing data supporting that the abrogation of TPL2 kinase activity ameliorates disease pathogenesis in a mouse model of tauopathy. This manuscript will be of broad interest to readers in the fields of neuroimmunology and neurodegenerative disease who are interested in the pathogenic effects of innate immune signaling pathways in disease.

eLife assessment

Rett syndrome is one of the most frequently diagnosed neurodevelopmental conditions. The gene mutated in the condition, Mecp2, encodes for a transcriptional repressor, but genes functioning downstream of Mecp2 have remained difficult to clarify. Here the authors identify an important candidate gene, Growth Differentiation Factor 11 (GDF11) regulated by Mecp2 via epigenetic mechanisms. Further studies in mouse models demonstrate that genetic reduction of Gdf11 ameliorates behavioral deficits of Mecp2 duplication mice, and can function to produce neurobehavioral deficits in mice alone. These findings will be of interest to scientists working in mouse cognition, behavior, neurodevelopment, transcriptional and epigenetics.