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Angelman syndrome (AS) is a neurogenetic disorder caused by deletion of the maternally inherited UBE3A allele and is characterized by developmental delay, intellectual disability, ataxia, seizures and a happy affect. Here, we explored the underlying pathophysiology using induced pluripotent stem cell-derived neurons from AS patients and unaffected controls. AS-derived neurons showed impaired maturation of resting membrane potential and action potential firing, decreased synaptic activity and reduced synaptic plasticity. These patient-specific differences were mimicked by knocking out UBE3A using CRISPR/Cas9 or by knocking down UBE3A using antisense oligonucleotides. Importantly, these phenotypes could be rescued by pharmacologically unsilencing paternal UBE3A expression. Moreover, selective effects of UBE3A disruption at late stages of in vitro development suggest that changes in action potential firing and synaptic activity may be secondary to altered resting membrane potential. Our findings provide a cellular phenotype for investigating pathogenic mechanisms underlying AS and identifying novel therapeutic strategies. Angelman syndrome (AS) is characterized by developmental delay and intellectual disability, but the underlying pathophysiology is not well understood. Here the authors use induced pluripotent stem cell-derived neurons from AS patients and find impaired maturation of resting membrane potential and action potential firing, and defects in synaptic activity associated with the disease.

Fragile X messenger ribonucleoprotein 1 protein (FMRP) binds many mRNA targets in the brain. The contribution of these targets to fragile X syndrome (FXS) and related autism spectrum disorder (ASD) remains unclear. Here, we show that FMRP deficiency leads to elevated microtubule-associated protein 1B (MAP1B) in developing human and non-human primate cortical neurons. Targeted MAP1B gene activation in healthy human neurons or MAP1B gene triplication in ASD patient-derived neurons inhibit morphological and physiological maturation. Activation of Map1b in adult male mouse prefrontal cortex excitatory neurons impairs social behaviors. We show that elevated MAP1B sequesters components of autophagy and reduces autophagosome formation. Both MAP1B knockdown and autophagy activation rescue deficits of both ASD and FXS patients’ neurons and FMRP-deficient neurons in ex vivo human brain tissue. Our study demonstrates conserved FMRP regulation of MAP1B in primate neurons and establishes a causal link between MAP1B elevation and deficits of FXS and ASD. MAP1B is bound and regulated by fragile X protein FMRP. Here, the authors show that elevated levels of MAP1B reduce the morphological and physiological maturation of human neurons and impair social behavior in mice.

Down syndrome, caused by trisomy 21, is a complex developmental disorder associated with intellectual disability and reduced growth of multiple organs. Structural pathologies are present at birth, reflecting embryonic origins. A fundamental unanswered question is how an extra copy of human chromosome 21 contributes to organ-specific pathologies that characterize individuals with Down syndrome, and, relevant to the hallmark intellectual disability in Down syndrome, how trisomy 21 affects neural development. We tested the hypothesis that trisomy 21 exerts effects on human neural development as early as neural induction. Bulk RNA sequencing was performed on isogenic trisomy 21 and euploid human induced pluripotent stem cells (iPSCs) at successive stages of neural induction: embryoid bodies at Day 6, early neuroectoderm at Day 10, and differentiated neuroectoderm at Day 17. Gene expression analysis revealed over 1,300 differentially expressed genes in trisomy 21 cells along the differentiation pathway compared to euploid controls. Less than 5% of the gene expression changes included upregulated chromosome 21 encoded genes at every timepoint. Genes involved in specific growth factor signaling pathways (WNT and Notch), metabolism (including oxidative stress), and extracellular matrix were altered in trisomy 21 cells. Further analysis uncovered heterochronic expression of genes. Trisomy 21 impacts discrete developmental pathways at the earliest stages of neural development. The results suggest that metabolic dysfunction arises early in embryogenesis in trisomy 21 and may affect development and function more broadly.

Significance Young neurons require occasional bursts of action-potential firing to maintain intracellular processes, to drive gene expression, to indicate their presence in a new location, and to attract and keep synaptic contacts. While in the adult cortex electrical activity is driven by synaptic inputs, during early cortical development these synaptic inputs are largely absent. In the absence of synaptic connections and sensory experience, human neurons use an energetically favorable membrane mechanism for generating and maintaining electrical activity: connexin hemichannels. The spontaneous flickering of connexin hemichannels produces depolarizing events (often crowned with bursts of action potentials) to help establish early electrical communication in young subplate neurons. This type of activity dominates the human cortical wall 5 months before birth.

Questions: What was the tree species composition of forests prior to European settlement at the northern hardwood range limit in eastern Québec, Canada? What role did human activities play in the changes in forest composition in this region? Location: Northern range limit of northern hardwoods in the Lower St. Lawrence region of eastern Québec, Canada. Methods: We used early land survey records (1846—1949) of public lands to reconstruct pre-settlement forest composition. The data consist of ranked tree species enumerations at points or for segments along surveyed lines, with enumerations of forest cover types and notes concerning disturbances. An original procedure was developed to weigh and combine these differing data types (line versus point observations; taxa versus cover enumerations). Change to present-day forest composition was evaluated by comparing survey records with forest decadal surveys conducted by the government of Québec over the last 30 years (1980—2009). Results: Pre-settlement dominance of conifers was strong and uniform across the study area, whereas dominance of maple and birches was patchy. Cedar and spruce were less likely to dominate with increasing altitude, whereas maple displayed the reverse trend. Frequency of disturbances, especially logging and fire, increased greatly after 1900. Comparison of survey records and modern plots showed general increases for maple (mentioned frequency increased by 39%), poplar (36%) and paper birch (31%). Considering only taxa ranked first by surveyors, cedar displayed the largest decrease (19%), whereas poplar (15%) and maple (9%) increased significantly. Conclusions: These changes in forest composition can be principally attributed to clear-cutting and colonization fire disturbances throughout the 20th century, and mostly reflected the propensity of taxa to expand (maples/aspen) or decline (cedar/spruce) with increased disturbance frequency. Québec's land survey archives provide an additional data source to reconstruct and validate our knowledge of North America's pre-settlement temperate and sub-boreal forests.

Mitochondrial fission and fusion are crucial for neurons. The RNA-binding protein FMRP regulates mitochondrial dynamics, including fusion and trafficking in neurons. A study now identifies a mechanism by which FMRP regulates mitochondrial fission.

Parvalbumin interneurons (PVIs) are affected in many psychiatric disorders including schizophrenia (SCZ), however the mechanism remains unclear. FXR1, a high confident risk gene for SCZ, is indispensable but its role in the brain is largely unknown. We show that deleting FXR1 from PVIs of medial prefrontal cortex (mPFC) leads to reduced PVI excitability, impaired mPFC gamma oscillation, and SCZ-like behaviors. PVI-specific translational profiling reveals that FXR1 regulates the expression of Cacna1h/Cav3.2 a T-type calcium channel implicated in autism and epilepsy. Inhibition of Cav3.2 in PVIs of mPFC phenocopies whereas elevation of Cav3.2 in PVIs of mPFC rescues behavioral deficits resulted from FXR1 deficiency. Stimulation of PVIs using a gamma oscillation-enhancing light flicker rescues behavioral abnormalities caused by FXR1 deficiency in PVIs. This work unveils the function of a newly identified SCZ risk gene in SCZ-relevant neurons and identifies a therapeutic target and a potential noninvasive treatment for psychiatric disorders.

One of the most important ways by which northern forests will respond to anticipated climate change is through variations in seed maturation. In this study, the relationship between growing degree-days (DD) >5°C and seed maturity was evaluated at three spatial scales. At the continental scale, the development of female gametophytes and embryos was evaluated as a function of the heat sums obtained from 11 sites distributed across the Canadian range of black spruce. At the regional scale, cone size and the percentage of germinated seeds formed in 1998, 1999, and 2000 were analyzed from seven sites situated along a latitudinal gradient in northern Quebec. At the local scale, cones were collected along perilacustral and insular transects according to their exposure to large water bodies, and from 10 islands located within a 2835-km2 hydroelectric reservoir. Our results confirm the 800—940 DD thermal sum threshold necessary for the complete maturation of black spruce embryos at several populations distributed across the total range of the species. Along the regional south-to-north climatic gradient, the percentage of germination can be predicted by a sigmoid function of a thermal sum (y = 2.8 + 25.1/[1 + e(x-896.6)/84.6]; r2 = 0.85, P < 0.0001) that attains a plateau at around 800—940 DD. Once the 800—940 DD threshold is attained, variations in the percentage of seed germination are mainly associated with inter-tree differences and local site factors (thickness of organic matter, tree density, tree height, tree age, and fetch). In the springtime, cold enclaves are created by the presence of the hydroelectric reservoir. The seed germination percentages in these enclaves varied from 0.6% ± 0.7% to 14.9% ± 19.1% (mean ± SD) according to the site (compared to 22.7% ± 15.1% for a site not exposed to the reservoir), which was equivalent to the germination percentages for sites at latitudes 1—3° farther north. These data suggest that the potential for black spruce regeneration increases strongly beyond the 800 DD isotherm, which evokes the possibility that subarctic open forests may become more dense under the current anticipated climate changes.

To assess the relationship between the regenerative potential of black spruce (Picea mariana (Mill.) BSP) and the latitudinal and thermal gradients, the cone crop was monitored in the same selection of trees during the 1989-1995 period in the northern boreal forest (sites A, n = 49, and B, n = 48), in the southern forest-tundra transition zone (site C, n = 35), and at the tree line (site D, n = 21). The size of the cone crop, the amount of seeds extracted per cone, along with the percentages of filled seed and germination were measured on each tree. There was no south to north trend associated with the cone crop. The cone crop at tree line was not significantly lower than in either of the southerly sites in six of the seven observed years. The number of seeds extracted per cone, the percentage of filled seeds, and the germination of filled seeds showed significant decrease northward according to year. Although there was no significant relationship between temperature and the cone production over the study area, the percentages of filled seeds and germination were significantly (0.51 r 2 0.44; p < 0.001) associated with the regional variation in heat sum.

In this review, we forcus on the biotic parameters that are crucial to an understanding of the recruitment dynamics of North American boreal tree species following natural (fire, budworm infestation, windthrow) or human-induced (clearcut, partial cut) disturbances. The parameters we emphasize are (i) the production of seeds and asexual stems (both of which, we argue, are a function of basal area density), (ii) the disperal of seeds by wind (or the dispersion of asexual stems) as a function of distance from source, (iii) dormant seed bank capacity, (iv) organic layer depth as a determinant of germinant mortality and asexual bud response, and (v) shade tolerance as a partial arbiter of the density of advance regeneration. Having identified the gaps in our knowledge, we conclude by suggesting a short-term research agenda whose completion would lead to the parameterized functions that would constitute the recruitment subroutine in a landscape-scale forest dynamics simulator.