Developmental Neurobiology最新文献

Neuron loss and disruption of neural circuits are associated with many neurological conditions. A key question is how to rebuild neural circuits for functional improvements. In vivo glia-to-neuron (GtN) conversion emerges as a potential solution for regeneration-based therapeutics. This approach takes advantage of the regenerative ability of resident glial cells to produce new neurons through cell fate reprogramming. Significant progress has been made over the years in this emerging field. However, inappropriate analysis often leads to misleading conclusions that create confusion and hype. In this perspective, we point out the most salient pitfalls associated with some recent studies and provide solutions to prevent them in the future. The goal is to foster healthy development of this promising field and lay a solid cellular foundation for future regeneration-based medicine.

Cerebral cortex development involves the sequential progression of biological steps driven by molecular pathways whose tight regulation often relies on ubiquitination. Ubiquitination is a posttranslational modification involved in all aspects of cellular homeostasis through the attachment of a ubiquitin (Ub) moiety on proteins. Over the past years, an increasing amount of research has highlighted the crucial role played by Ub ligases in every step of cortical development and whose impairment often leads to various neurodevelopmental disorders. In this review, we focus on the key contributions of E3 Ub ligases for the progression of the different steps of corticogenesis, as well as the pathological consequences of their mutations, often resulting in malformations of cortical development. Finally, we discuss some promising therapeutic strategies for these diseases based on recent advances in the field.

Golden Retriever dogs with a frameshift variant in CLN5 (c.934_935delAG) suffer from a progressive neurodegenerative disorder analogous to the CLN5 form of neuronal ceroid lipofuscinosis (NCL). Five littermate puppies homozygous for the deletion allele were identified prior to the onset of disease signs. Studies were performed to characterize the onset and progression of the disease in these dogs. Neurological signs that included restlessness, unwillingness to cooperate with the handlers, and proprioceptive deficits first became apparent at approximately 12 months of age. The neurological signs progressed over time and by 21 to 23 months of age included general proprioceptive ataxia, menace response deficits, aggressive behaviors, cerebellar ataxia, intention tremors, decreased visual tracking, seizures, cognitive decline, and impaired prehension. Due to the severity of these signs, the dogs were euthanized between 21 and 23 months of age. Magnetic resonance imaging revealed pronounced progressive global brain atrophy with a more than sevenfold increase in the volume of the ventricular system between 9.5 and 22.5 months of age. Accompanying this atrophy were pronounced accumulations of autofluorescent inclusions throughout the brain and spinal cord. Ultrastructurally, the contents of these inclusions were found to consist primarily of membrane-like aggregates. Inclusions with similar fluorescence properties were present in cardiac muscle. Similar to other forms of NCL, the affected dogs had low plasma carnitine concentrations, suggesting impaired carnitine biosynthesis. These data on disease progression will be useful in future studies using the canine model for therapeutic intervention studies.

Retinal ganglion cells generate a pattern of action potentials to communicate visual information from the retina to cortical areas. Myelin, an insulating sheath, wraps axonal segments to facilitate signal propagation and when deficient, can impair visual function. Optic nerve development and initial myelination has largely been considered completed by the fifth postnatal week. However, the relationship between the extent of myelination and axonal signaling in the maturing optic nerve is not well characterized. Here, we examine the relationship between axon conduction and elements of myelination using extracellular nerve recordings, immunohistochemistry, western blot analysis, scanning electron microscopy, and simulations of nerve responses. Comparing compound action potentials from mice aged 4–12 weeks revealed five functional distinct axonal populations, an increase in the number of functional axons, and shifts toward fast-conducting axon populations at 5 and 8 weeks postnatal. At these ages, our analysis revealed increased myelin thickness, lower g-ratios and changes in the 14 kDa MBP isoform, while the density of axons and nodes of Ranvier remained constant. At 5 postnatal weeks, axon diameter increased, while at 8 weeks, increased expression of a mature sodium ion channel subtype, Na_v 1.6, was observed at nodes of Ranvier. A simulation model of nerve conduction suggests that ion channel subtype, axon diameter, and myelin thickness are more likely to be key regulators of nerve function than g-ratio. Such refinement of axonal function and myelin rearrangement identified an extended period of maturation in the normal optic nerve that may facilitate the development of visual signaling patterns.

Intracortical myelin is thought to play a significant role in the development of neural circuits and functional networks, with consistent evidence of atypical network connectivity in children with autism spectrum disorder (ASD). However, little is known about the development of intracortical myelin in the first years of life in ASD, during the critical neurodevelopmental period when autism symptoms first emerge. Using T1-weighted (T1w) and T2w structural magnetic resonance imaging (MRI) in 21 young children with ASD and 16 typically developing (TD) children, ages 1.5–5.5 years, we demonstrate the feasibility of estimating intracortical myelin in vivo using the T1w/T2w ratio as a proxy. The resultant T1w/T2w maps were largely comparable with those reported in prior T1w/T2w studies in TD children and adults, and revealed no group differences between TD children and those with ASD. However, differential associations between T1w/T2w and age were identified in several early myelinated regions (e.g., visual, posterior cingulate, precuneus cortices) in the ASD and TD groups, with age-related increase in estimated myelin content across the toddler and preschool years detected in TD children, but not in children with ASD. The atypical age-related effects in intracortical myelin, suggesting a disrupted myelination in the first years of life in ASD, may be related to the aberrant brain network connectivity reported in young children with ASD in some of the same cortical regions and circuits.

Excessive smartphone use has been repeatedly related to adverse effects on mental health and psychological well-being in young adults. The continued investigation of the neurobiological mechanism underlying excessive smartphone use—sometimes also referred to as “smartphone addiction”(SPA)—is considered a top priority in system neuroscience research. Despite progress in the past years, cortical morphology associated with SPA is still poorly understood. Here, we used structural magnetic resonance imaging (MRI) at 3 T to investigate two cortical surface markers of distinct neurodevelopmental origin such as the complexity of cortical folding (CCF) and cortical thickness (CTh) in individuals with excessive smartphone use (n = 19) compared to individuals not fulfilling SPA criteria (n-SPA; n = 22). SPA was assessed using the Smartphone Addiction Inventory (SPAI). CCF and CTh were investigated using the Computational Anatomy Toolbox (CAT12). SPA individuals showed lower CCF in the right superior frontal gyrus as well as in the right caudal (cACC) and rostral anterior cingulate cortex (rACC) compared to n-SPA individuals (TFCE, uncorrected at p < 0.001). Following a dimensional approach, across the entire sample, CCF of the right cACC was significantly associated with SPAI total score, as well as with distinct SPAI subdimensions, particularly time spent with the device, compulsivity, and sleep interference in all participants (n = 41; p < 0.05, FDR-corrected). Collectively, these findings suggest that SPA is associated with aberrant structural maturation of regions important for cognitive control and emotional regulation.

Axons are the long and slender processes of neurons constituting the biological cables that wire the nervous system. The growth and maintenance of axons require loose microtubule bundles that extend through their entire length. Understanding microtubule regulation is therefore an essential aspect of axon biology. Key regulators of neuronal microtubules are the spectraplakins, a well-conserved family of cytoskeletal cross-linkers that underlie neuropathies in mouse and humans. Spectraplakin deficiency in mouse or Drosophila causes severe decay of microtubule bundles and reduced axon growth. The underlying mechanisms are best understood for Drosophila’s spectraplakin Short stop (Shot) and believed to involve cytoskeletal cross-linkage: Shot's binding to microtubules and Eb1 via its C-terminus has been thoroughly investigated, whereas its F-actin interaction via N-terminal calponin homology (CH) domains is little understood. Here, we have gained new understanding by showing that the F-actin interaction must be finely balanced: altering the properties of F-actin networks or deleting/exchanging Shot's CH domains induces changes in Shot function—with a Lifeact-containing Shot variant causing remarkable remodeling of neuronal microtubules. In addition to actin-microtubule (MT) cross-linkage, we find strong indications that Shot executes redundant MT bundle-promoting roles that are F-actin-independent. We argue that these likely involve the neuronal Shot-PH isoform, which is characterized by a large, unexplored central plakin repeat region (PRR) similarly existing also in mammalian spectraplakins.

Developmental neural activity is a common feature of neural circuit assembly. Although glia have established roles in synapse development, the contribution of neuron–glia interactions to developmental activity remains largely unexplored. Here we show that astrocytes are necessary for developmental activity during synaptogenesis in Drosophila. Using wide-field epifluorescence and two-photon imaging, we show that the glia of the central nervous system participate in developmental activity with type-specific patterns of intracellular calcium dynamics. Genetic ablation of astrocytes, but not of cortex or ensheathing glia, leads to severe attenuation of neuronal activity. Similarly, inhibition of neuronal activity results in the loss of astrocyte calcium dynamics. By altering these dynamics, we show that astrocytic calcium cycles can influence neuronal activity but are not necessary per se. Taken together, our results indicate that, in addition to their recognized role in the structural maturation of synapses, astrocytes are also necessary for the function of synapses during development.

Protein arginine methylation has been recognized as one of key posttranslational modifications for refined protein functions, mediated by protein arginine methyltransferases (Prmts). Coactivator-associated arginine methyltransferase (Carm1, also known as Prmt4) participates in various cellular events, such as cell survival, proliferation, and differentiation through its protein arginine methylation activities. Carm1 regulates cell proliferation of a neuronal cell line and is reportedly expressed in the mammalian brain. However, its detailed function in the central nervous system, particularly in glial cells, remains largely unexplored. In this study, Carm1 exhibited relatively high expression in oligodendrocyte (OL) lineage cells present in the corpus callosum of the developing brain, followed by a remarkable downregulation after active myelination. The suppression of Carm1 activity by inhibitors in isolated oligodendrocyte precursor cells (OPCs) reduced the number of Ki67-expressing and BrdU-incorporated proliferating cells. Furthermore, Carm1 inactivation attenuated OL differentiation, as determined by the expression of Plp, a reliable myelin-related marker. It also impaired the extension of OL processes, accompanied by a significant reduction in gene expression related to OL differentiation and myelination, such as Sox10, Cnp, Myrf, and Mbp. In addition, OLs co-cultured with embryonic dorsal root ganglia neurons demonstrated that Carm1 activity is required for the appropriate formation of myelin processes and myelin sheaths around neuronal axons, and the induction of the clustering of Caspr, a node of Ranvier structural molecule. Thus, we propose that Carm1 is an essential molecule for the development of OPCs and OLs during brain development.