Shaping The Brain By Neuronal Cytoskeleton From Development To Disease And Regeneration

Shaping the Brain by Neuronal Cytoskeleton: from Development to Disease and Regeneration

Neurobiology of the Axon in Health and Disease

Ever since Santiago Ramón y Cajal sketched his captivating panels of the microscopic structure of the brain with its vast diversity of neuronal morphology over a century ago, scientists have been drawn to this seemingly chaotic network of neurites and processes to uncover how structure relates to function. During the course of a century, we have moved from merely describing neuronal and glial morphology to furthering our understanding of such intricate processes as organelle and factor transport, cellular compartmentalization, neuronal polarity, cytoskeleton dynamics, neurite pathfinding, and the impact of pathophysiological insult on these structures and events. Yet to this day, and likely for the foreseeable future, much work remains to be done to fully grasp the exceptional role of neurites for the function of larger neuronal ensembles and networks. While the somatodendritic domain of neurons has been in the focus of attention for many years, mostly because of its great dynamic remodeling capacity during events of plasticity (e.g. learning), the axonal domain has somehow remained in the background despite the fact that especially recent comprehensive studies from various fields of research underline the axon’s contribution to dynamic plasticity processes. Consequently, this Research Topic focuses on the many exciting aspects of axonal neurobiology – ranging from membrane composition and molecular determination during development to axonal domain specialization and physiology in health and disease. In Chapter 1 “Axons in the PNS”, Bombeiro et al. use immunodeficient mice to study the role of lymphocytes during the regeneration of peripheral nerves, showing that the modulation of immune responses after injury can be an efficient approach to enhance nerve regeneration in the PNS. Using a DRG model, Berbusse et al. identify the onset of damage to mitochondrial structure and dynamics as a key event during early axon degeneration and provide evidence that Nmnat1, a member of the family of nicotinamide-nucleotide adenylyltransferases, can have protective effects by preserving normal mitochondrial integrity and dynamics. In another study of PNS nerve regeneration, Law et al. use proteomics approaches via Mass Spectrometry to provide evidence that rosovitine, a synthetic purine nucleoside analog, can successfully promote PNS axon regeneration. In Chapter 2 “Axonal development in the central nervous system”, Yoshimura et al. analyze specialized axonal domains, namely the axon initial segment and nodes of Ranvier, with regards to their expression profiles of the major scaffolding protein ßIV-spectrin. Super resolution microscopy reveals a potential developmental switch of spectrin isoforms at both axonal domains. In a related study, also using super resolution microscopy, Leterrier et al. examine a potential reciprocal role of membrane partners in ankyrin-G targeting and stabilization at the axonal membrane during development. The authors demonstrate a tight and precocious association of ankyrin-G with its membrane partners. Höfflin et al. address the question of axon initial segment morphology across different cell classes in cortical organotypic slice cultures and find a surprising heterogeneity especially between pyramidal cells and interneurons in primary visual cortex. In a major step towards establishing a successful live label of the axon initial segment, Dumitrescu et al. report the development of a genetically-encoded construct consisting of a voltage-gated sodium channel intracellular domain fused to yellow fluorescent protein (YFP-NaVII-III). Nelson and Jenkins then provide a comprehensive Review article on the axon initial segment and nodes of Ranvier with a special focus on the various scaffolding protein isoforms and their role in human disease. In Chapter 3 “Axonal physiology and plasticity”, Nikitin et al. investigate fast onset dynamics of action potentials during neuronal development in vitro, showing that encoding of high frequencies improves upon culture maturation, accompanied by the development of passive electrophysiological properties and action potential generation. Using pharmacological and RNA interference approaches, Tapia et al. provide evidence that cannabinoid receptors and their ligands can modulate dendritic morphology and thus, indirectly, also affect ankyrin-G accumulation at the axon initial segment. A Mini Review by Zbili et al. discusses the potential impact of subthreshold changes in presynaptic membrane potential before action potential initiation on neurotransmitter release, and which significant impact such mechanisms could have on information processing in neuronal circuits. Yamada and Kuba close this chapter with a Mini Review on axon initial segment plasticity with a particular focus on ion channels and the biophysics of excitability. In Chapter 4 “Axon degeneration and regeneration”, Hamada et al. investigate the often overlooked question to which extent myelin loss affects action potential propagation along distal branch points and axon collaterals. Using the cuprizone demyelination model and optical voltage-sensitive dye imaging, the authors uncover functional consequences of demyelination that reach well beyond the main axon. In a model of mild traumatic brain injury, Vascak et al. demonstrate complex aspects of this injury type on neocortical circuit function, including changes in inhibitory perisomatic input and axon initial segment-driven output in affected layer V neurons. In a Mini Review, Grosch et al. discuss recent advances in the field of Parkinson’s disease with a focus on early degeneration in dopaminergic and serotonergic neurons of the basal ganglia. The last two articles cover the topic of axonal regeneration. Li et al. investigate the role of activated astrocytes in spinal cord lesion and how their functional downregulation via an inhibitor of mitochondrial fission, Mdivi-1, could potentially have positive impact on lesion scar formation and axonal regeneration. In a final Review, Liu et al. highlight recent advances in the development of biomaterial scaffolds and cell transplantation strategies to combine two promising therapeutic approaches for spinal cord injury.

Neuronal Self-Defense: Compensatory Mechanisms in Neurodegenerative Disorders

Neurodegenerative disorders are characterized by the progressive loss of specific populations of neurons with consequent deterioration of brain's function and dramatic impact on human behavior. At present, there are no effective cures for neurodegenerative diseases. Because unambiguous diagnosis is possible only after manifestation of symptoms, when a large proportion of neurons has been already lost, therapies are necessarily confined to alleviation of symptoms. Development of cures halting the disease course is hampered by our rudimentary understanding of the etiopathology. Most neurodegenerative disorders are sporadic and age-related and - even for those of known genetic origin - the mechanisms influencing disease onset and progression have not been fully characterized. The different diseases, however, share important similarities in the mechanisms responsible for neuronal loss, which is caused by a combination of endogenous and exogenous challenges. Trophic deprivation, oxidative stress, accumulation of abnormal protein aggregates, and bioenergetics defects have been described in most, if not all, neurodegenerative disease. To counterbalance these noxious stimuli cells deploy, at least during the initial pathogenic states, intrinsic neuroprotective responses. These are general compensatory mechanisms, common to several neurodegenerative conditions, which reprogram cellular physiology to overcome stress. Adaptation includes strategies to optimize energetic resources, for instance reduction of rRNA synthesis to repress translation, suppression of transcription, and bioenergetics and metabolic redesign. Additional mechanisms include potentiation of antioxidant capacity, induction of endoplasmic reticulum (ER) stress, and activation of protein quality control systems and autophagy. Ineffective execution of these compensatory strategies severely threatens cellular homeostasis and favors onset of pathology. Therefore, a better understanding of these "buffering" mechanisms and of their interconnections may help to devise more effective therapeutic tools to prolong neuronal survival and activity, independently of the original genetic mutations and stress insults. This Research Topic focuses on the initial compensatory responses protecting against failure of those mechanisms that sustain neuronal survival and activity. The collection intends to summarize the state-of-the-art in this field and to propose novel research contributes, with the ultimate goal of inspiring innovative studies aimed to contrast progression of neurodegenerative diseases.