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Alzheimer´s disease (AD) is characterized by neuronal function loss and degeneration. The integrity of the axon initial segment (AIS) is essential to maintain neuronal function and output. AIS alterations are detected in human post-mortem AD brains and mice models, as well as, neurodevelopmental and mental disorders. However, the mechanisms leading to AIS deregulation in AD and the extrinsic glial origin are elusive. We studied early postnatal differences in AIS cellular/molecular mechanisms in wild-type or APP/PS1 mice and combined neuron-astrocyte co-cultures. We observed AIS integrity alterations, reduced ankyrinG expression and shortening, in APP/PS1 mice from P21 and loss of AIS integrity at 21 DIV in wild-type and APP/PS1 neurons in the presence of APP/PS1 astrocytes. AnkyrinG decrease is due to mRNAs and protein reduction of retinoic acid synthesis enzymes Rdh1 and Aldh1b1, as well as ADNP (Activity-dependent neuroprotective protein) in APP/PS1 astrocytes. This effect was mimicked by wild-type astrocytes expressing ADNP shRNA. In the presence of APP/PS1 astrocytes, wild-type neurons AIS is recovered by inhibition of retinoic acid degradation, and Adnp-derived NAP peptide (NAPVSIPQ) addition or P2X7 receptor inhibition, both regulated by retinoic acid levels. Moreover, P2X7 inhibitor treatment for 2 months impaired AIS disruption in APP/PS1 mice. Our findings extend current knowledge on AIS regulation, providing data to support the role of astrocytes in early postnatal AIS modulation. In conclusion, AD onset may be related to very early glial cell alterations that induce AIS and neuronal function changes, opening new therapeutic approaches to detect and avoid neuronal function loss. [ABSTRACT FROM AUTHOR]

Neuroinvasive infection is the most common cause of meningoencephalitis in people living with human immunodeficiency virus (HIV), but autoimmune etiologies have been reported. We present the case of a 51-year-old man living with HIV infection with steroid-responsive meningoencephalitis whose comprehensive pathogen testing was non-diagnostic. Subsequent tissue-based immunofluorescence with acute-phase cerebrospinal fluid revealed anti-neural antibodies localizing to the axon initial segment (AIS), the node of Ranvier (NoR), and the subpial space. Phage display immunoprecipitation sequencing identified ankyrinG (AnkG) as the leading candidate autoantigen. A synthetic blocking peptide encoding the PhIP-Seq-identified AnkG epitope neutralized CSF IgG binding to the AIS and NoR, thereby confirming a monoepitopic AnkG antibody response. However, subpial immunostaining persisted, indicating the presence of additional autoantibodies. Review of archival tissue-based staining identified candidate AnkG autoantibodies in a 60-year-old woman with metastatic ovarian cancer and seizures that were subsequently validated by cell-based assay. AnkG antibodies were not detected by tissue-based assay and/or PhIP-Seq in control CSF (N = 39), HIV CSF (N = 79), or other suspected and confirmed neuroinflammatory CSF cases (N = 1,236). Therefore, AnkG autoantibodies in CSF are rare but extend the catalog of AIS and NoR autoantibodies associated with neurological autoimmunity.

Neuroinvasive infection is the most common cause of meningoencephalitis in people living with human immunodeficiency virus (HIV), but autoimmune etiologies have been reported. We present the case of a 51-year-old man living with HIV infection with steroid-responsive meningoencephalitis whose comprehensive pathogen testing was non-diagnostic. Subsequent tissue-based immunofluorescence with acute-phase cerebrospinal fluid revealed anti-neural antibodies localizing to the axon initial segment (AIS), the node of Ranvier (NoR), and the subpial space. Phage display immunoprecipitation sequencing identified ankyrinG (AnkG) as the leading candidate autoantigen. A synthetic blocking peptide encoding the PhIP-Seq-identified AnkG epitope neutralized CSF IgG binding to the AIS and NoR, thereby confirming a monoepitopic AnkG antibody response. However, subpial immunostaining persisted, indicating the presence of additional autoantibodies. Review of archival tissue-based staining identified candidate AnkG autoantibodies in a 60-year-old woman with metastatic ovarian cancer and seizures that were subsequently validated by cell-based assay. AnkG antibodies were not detected by tissue-based assay and/or PhIP-Seq in control CSF (N = 39), HIV CSF (N = 79), or other suspected and confirmed neuroinflammatory CSF cases (N = 1,236). Therefore, AnkG autoantibodies in CSF are rare but extend the catalog of AIS and NoR autoantibodies associated with neurological autoimmunity.

The axon initial segment (AIS) plays an important role in maintaining neuronal polarity and initiating action potentials (APs). The AIS adapts to its environment by changing its length and distance from the cell body, resulting in modulation of neuronal excitability, which is referred to as AIS plasticity. Previous studies found an ~200 nm single periodic distribution of the key AIS components ankyrinG (AnkG), Nav1.2, and βIV‐spectrin, while it remains unclear how the lattice structure is altered by AIS plasticity. In this study, we found that the length of the AIS significantly increased, resulting in increased neuronal excitability, with high‐concentration glucose treatment. Structured illumination microscopy (SIM) images of the lattice structure showed a dual‐spacing periodic distribution (~200 nm and ~260 nm) of AnkG, Nav1.2, and βIV‐spectrin. Moreover, 480‐kDa AnkG was crucial for AIS plasticity and increased lattice structure spacing. The discovery of new regulators for modulating AIS plasticity will help us to understand and manipulate the structure and function of the AIS. Glucose triggers axon initial segment (AIS) plasticity of cultured neurons.AIS lattice structure under glucose treatment shows an increased spacing by structured illumination microscopy imaging.480‐kDa AnkG contributes to AIS plasticity. [ABSTRACT FROM AUTHOR]

The axon initial segment (AIS) is essential for maintaining neuronal polarity, modulating protein transport into the axon, and action potential generation. These functions are supported by a distinctive actin and microtubule cytoskeleton that controls axonal trafficking and maintains a high density of voltage-gated ion channels linked by scaffold proteins to the AIS cytoskeleton. However, our knowledge of the mechanisms and proteins involved in AIS cytoskeleton regulation to maintain or modulate AIS structure is limited. In this context, formins play a significant role in the modulation of actin and microtubules. We show that pharmacological inhibition of formins modifies AIS actin and microtubule characteristics in cultured hippocampal neurons, reducing F-actin density and decreasing microtubule acetylation. Moreover, formin inhibition diminishes sodium channels, ankyrinG and βIV-spectrin AIS density, and AIS length, in cultured neurons and brain slices, accompanied by decreased neuronal excitability. We show that genetic downregulation of the mDia1 formin by interference RNAs also decreases AIS protein density and shortens AIS length. The ankyrinG decrease and AIS shortening observed in pharmacologically inhibited neurons and neuron-expressing mDia1 shRNAs were impaired by HDAC6 downregulation or EB1-GFP expression, known to increase microtubule acetylation or stability. However, actin stabilization only partially prevented AIS shortening without affecting AIS protein density loss. These results suggest that mDia1 maintain AIS composition and length contributing to the stability of AIS microtubules. [ABSTRACT FROM AUTHOR]

Morphological and functional polarization of neurons depends on the generation and maintenance of the axon initial segment (AIS). This axonal domain maintains axonal properties but is also the place where the action potential (AP) is generated. All these functions require the AIS, a complex structure that is not fully understood. An integrated structure of voltage-gated ion channels, specific cytoskeleton architecture, as well as, scaffold proteins contributes to these functions. Among them, ankyrinG plays a crucial role to maintain ion channels and membrane proteins. However, it is still elusive how the AIS performs its complex structural and functional regulation. Recent studies reveal that AIS is dynamically regulated in molecular composition, length and location in response to neuronal activity. Some mechanisms acting on AIS plasticity have been uncovered recently, including Ca2+, calpain or calmodulin-mediated modulation, as well as post-translational modifications of cytoskeleton proteins and actin-associated proteins. Neurons are able to respond to different kind of physiological and pathological stimuli from development to maturity by adapting their AIS composition, position and length. This raises the question of which are the neuronal receptors that contribute to the modulation of AIS plasticity. Previous studies have shown that purinergic receptor P2X7 activation is detrimental to AIS maintenance. During initial axonal elongation, P2X7 is coordinated with P2Y1, another purinergic receptor that is essential for proper axon elongation. In this study, we focus on the role of P2Y1 receptor on AIS development and maintenance. Our results show that P2Y1 receptor activity and expression are necessary during AIS initial development, while has no role once AIS maturity is achieved. P2Y1 inhibition or suppression results in a decrease in ankyrinG, βIV-spectrin and voltage-gated sodium channels accumulation that can be rescued by actin stabilization or the modulation of actin-binding proteins at the AIS. Moreover, P2X7 or calpain inhibition also rescues ankyrinG decrease. Hence, a dynamic balance of P2Y1 and P2X7 receptors expression and function during AIS assembly and maturation may represent a fine regulatory mechanism in response to physiological or pathological extracellular purines concentration.

Morphological and functional polarization of neurons depends on the generation and maintenance of the axon initial segment (AIS). This axonal domain maintains axonal properties but is also the place where the action potential (AP) is generated. All these functions require the AIS, a complex structure that is not fully understood. An integrated structure of voltage-gated ion channels, specific cytoskeleton architecture, as well as, scaffold proteins contributes to these functions. Among them, ankyrinG plays a crucial role to maintain ion channels and membrane proteins. However, it is still elusive how the AIS performs its complex structural and functional regulation. Recent studies reveal that AIS is dynamically regulated in molecular composition, length and location in response to neuronal activity. Some mechanisms acting on AIS plasticity have been uncovered recently, including Ca2+, calpain or calmodulin-mediated modulation, as well as post-translational modifications of cytoskeleton proteins and actin-associated proteins. Neurons are able to respond to different kind of physiological and pathological stimuli from development to maturity by adapting their AIS composition, position and length. This raises the question of which are the neuronal receptors that contribute to the modulation of AIS plasticity. Previous studies have shown that purinergic receptor P2X7 activation is detrimental to AIS maintenance. During initial axonal elongation, P2X7 is coordinated with P2Y1, another purinergic receptor that is essential for proper axon elongation. In this study, we focus on the role of P2Y1 receptor on AIS development and maintenance. Our results show that P2Y1 receptor activity and expression are necessary during AIS initial development, while has no role once AIS maturity is achieved. P2Y1 inhibition or suppression results in a decrease in ankyrinG, βIV-spectrin and voltage-gated sodium channels accumulation that can be rescued by actin stabilization or the modulation of actin-binding proteins at the AIS. Moreover, P2X7 or calpain inhibition also rescues ankyrinG decrease. Hence, a dynamic balance of P2Y1 and P2X7 receptors expression and function during AIS assembly and maturation may represent a fine regulatory mechanism in response to physiological or pathological extracellular purines concentration. [ABSTRACT FROM AUTHOR]

Highlights • Exon 34 of AnkyrinG is differentially spliced during development. • Elavl3 protein promotes the exclusion of exon 34 of AnkyrinG. • Exon 34 of AnkyrinG affects AnkyrinG localization and function. • Exon 34 of AnkyrinG was acquired during vertebrate evolution. Abstract Alternative splicing of RNAs diversifies the functionalities of proteins, and it is optimized for each cell type and each developmental stage. nElavl (composed of Elavl2, Elavl3, and Elavl4) proteins are the RNA-binding proteins that is specifically expressed in neurons, regulate the alternative splicing of target RNAs, and promote neuronal differentiation and maturation. Recent studies revealed that Elavl3 knockout (Elavl3 −/−) mice completely lost the expression of nElavl proteins in the Purkinje cells and exhibited cerebellar dysfunction. Here, we found that the alternative splicing of AnkyrinG exon 34 was misregulated in the cerebella of Elavl3 −/− mice. AnkyrinG is an essential factor for the formation of neuronal polarity and is required for normal neuronal functions. We revealed that exon 34 of AnkyrinG was normally included in immature neurons and was mostly excluded in mature neurons; however, it was included in the cerebella of Elavl3 −/− mice even in adulthood. In the Purkinje cells of adult Elavl3 −/− mice, the length of the AnkyrinG-positive region shortened and somatic organelles leaked into the axons. These results suggested that exon 34 of AnkyrinG is an embryonic-stage-preferential exon that should be excluded from mature neurons and that Elavl3 regulates neuronal polarity through alternative splicing of this exon. [ABSTRACT FROM AUTHOR]

ANK3 encodes AnkyrinG (AnkG), a member of the Ankyrin family that is expressed in several different isoforms in many tissues. A unique serine-rich domain and tail domain in the two largest isoforms of AnkG (270 and 480 kDa), restrict AnkG to the axon initial segment and nodes of Ranvier of myelinated neurons. At these sites, AnkG is a master regulator, coordinating the strict clustering of components necessary for proper action potential initiation and propagation along the axon. These components include voltage-gated sodium channels, potassium channels and members of the L1 cell adhesion molecule family. Genetic variation in the ANK3 gene has been linked to a range of neuropsychiatric and neurodevelopmental disorders in human, including schizophrenia, bipolar disorder, intellectual disability and autism spectrum disorders. Here, we study the effect of reduced expression of the large isoforms of Ank3 on cognition and behaviour using a heterozygous knockout mouse model. In three independent behavioural tests, being the open field test, elevated plus maze and social interaction test, we found evidence for increased anxiety in our Ank3 mouse model. Besides, we observed specific neuroanatomical defects in heterozygous knockout mice, including a smaller cingulate cortex, granular retrosplenial cortex, primary motor cortex and fimbria of the hippocampus. [ABSTRACT FROM AUTHOR]

Neuronal polarization underlies the ability of neurons to integrate and transmit information. This process begins early in development with axon outgrowth, followed by dendritic growth and subsequent maturation. In between these two steps, the axon initial segment (AIS), a subcellular domain crucial for generating action potentials (APs) and maintaining the morphological and functional polarization, starts to develop. However, the cellular/molecular mechanisms and receptors involved in AIS initial development and maturation are mostly unknown. In this study, we have focused on the role of the type-1 cannabinoid receptor (CB1R), a highly abundant G-protein coupled receptor (GPCR) in the nervous system largely involved in different phases of neuronal development and differentiation. Although CB1R activity modulation has been related to changes in axons or dendrites, its possible role as a modulator of AIS development has not been yet explored. Here we analyzed the potential role of CB1R on neuronal morphology and AIS development using pharmacological and RNA interference approaches in cultured hippocampal neurons. CB1R inhibition, at a very early developmental stage, has no effect on axonal growth, yet CB1R activation can promote it. By contrast, subsequent dendritic growth is impaired by CB1R inhibition, which also reduces ankyrinG density at the AIS. Moreover, our data show a significant correlation between early dendritic growth and ankyrinG density. However, CB1R inhibition in later developmental stages after dendrites are formed only reduces ankyrinG accumulation at the AIS. In conclusion, our data suggest that neuronal CB1R basal activity plays a role in initial development of dendrites and indirectly in AIS proteins accumulation. Based on the lack of CB1R expression at the AIS, we hypothesize that CB1R mediated modulation of dendritic arbor size during early development indirectly determines the accumulation of ankyrinG and AIS development. Further studies will be necessary to determine which CB1R-dependent mechanisms can coordinate these two domains, and what may be the impact of these early developmental changes once neurons mature and are embedded in a functional brain network. [ABSTRACT FROM AUTHOR]

The axon initial segment (AIS) is responsible for both the modulation of action potentials and the maintenance of neuronal polarity. Yet, the molecular mechanisms controlling its assembly are incompletely understood. Our study in single electroporated motor neurons in mouse embryos revealed that AnkyrinG (AnkG), the AIS master organizer, is undetectable in bipolar migrating motor neurons, but is already expressed at the beginning of axonogenesis at E9.5 and initially distributed homogeneously along the entire growing axon. Then, from E11.5, a stage when AnkG is already apposed to the membrane, as observed by electron microscopy, the protein progressively becomes restricted to the proximal axon. Analysis on the global motor neurons population indicated that Neurofascin follows an identical spatio-temporal distribution, whereas sodium channels and β4-spectrin only appear along AnkG segments at E11.5. Early patch-clamp recordings of individual motor neurons indicated that at E12.5 these nascent AISs are already able to generate spikes. Using knock-out mice, we demonstrated that neither β4-spectrin nor Neurofascin control the distal-to-proximal restriction of AnkG. [ABSTRACT FROM AUTHOR]

The axon initial segment (AIS) is the site of spike initiation in neurons. Previous studies revealed that spatial distribution of the AIS varies greatly among neurons to meet their specific needs. However, when and how this differentiation arises is unknown. Neurons in the avian nucleus laminaris (NL) are binaural coincidence detectors for sound localization and show differentiation in the distribution of the AIS, with shorter length and a more distal position from the soma with an increase in tuning frequency. We studied these characteristics of the AIS in NL neurons of the chicken during development and found that the AIS differentiates in its distribution after initial formation, and this is driven by activity-dependent and activity-independent mechanisms that differentially regulate distal and proximal boundaries of the AIS. Before hearing onset, the ankyrinG-positive AIS existed at a wide stretch of proximal axon regardless of tuning frequency, but Na+channels were only partially distributed within the AIS. Shortly after hearing onset, Na+channels accumulated along the entire AIS, which started shortening and relocating distally to a larger extent in neurons with higher tuning frequencies. Ablation of inner ears abolished the shortening of the AIS without affecting the position of its proximal boundary, indicating that both distal and proximal AIS boundaries are disassembled during development, and the former is dependent on afferent activity. Thus, interaction of these activitydependent and activity-independent mechanisms determines the cell-specific distribution of the AIS in NL neurons and plays a critical role in establishing the function of sound localization circuit. [ABSTRACT FROM AUTHOR]

Doyle GA, Lai AT, Chou AD, Wang M-J, Gai X, Rappaport EF, Berrettini WH. Re-sequencing of ankyrin 3 exon 48 and case-control association analysis of rare variants in bipolar disorder type I. Bipolar Disord 2012: 14: 809-821. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Genome-wide association studies (GWAS) recently identified ankyrin 3 ( ANK3) as a candidate gene for bipolar disorder type I (BPD-I). Because the GWAS suggested multiple common haplotypes associated with BPD-I (with odds ratio ∼1.3), we hypothesized that rare variants within these common haplotypes might increase risk for BPD-I. Methods: We undertook a project in which the serine-rich domain-tail domain (SRD-TD)-encoding exon of ANK3 was amplified from genomic DNA (gDNA) of 384 BPD-I patients and re-sequenced by next generation sequencing (NGS; SOLiD™). Results: We confirmed 18 novel mis-sense rare variants and one novel insertion/deletion variant within the SRD-TD exon, many of which change amino acid residues with extremely high evolutionary conservation. We genotyped most of these mis-sense variants in ≥ 1000 BPD-I and ≥ 1000 control individuals. We found no statistically significant association of any of the rare variants detected with BPD-I. Conclusions: Thus, we conclude that rare variants within the re-sequenced structural domains of ANK3 exon 48 do not contribute to BPD-I. [ABSTRACT FROM AUTHOR]

Abstract: The inhibitor of NF-κB alpha (IκBα) protein is an important regulator of the transcription factor NF-κB. In neurons, IκBα has been shown to play a role in neurite outgrowth and cell survival. Recently, a phosphorylated form of IκBα (pIκBα Ser32/36) was reported to be highly enriched at the axon initial segment (AIS) and was proposed to function upstream of ankyrinG in AIS assembly, including ion channel recruitment. However, we report here that the AIS clustering of ankyrinG and Na+ channels in the brains of IκBα knockout (Nfkbia −/−) mice is comparable to that in wild-type littermates. Furthermore, we found that multiple phospho-specific antibodies against pIκBα Ser32/36 non-specifically label AIS in Nfkbia −/− cortex and AIS in dissociated Nfkbia −/− hippocampal neurons. With the exception of ankyrinG, shRNA-mediated knockdown of known AIS proteins in cultured hippocampal neurons did not eliminate the AIS labeling with pIκBα antibodies. Instead, the pIκBα antibodies cross-react with a phosphorylated epitope of a protein associated with the microtubule-based AIS cytoskeleton that is not integrated into the AIS membrane complex organized by ankyrinG. Our results indicate that pIκBα is neither enriched at the AIS nor required for AIS assembly. [Copyright &y& Elsevier]

Abstract: The axon initial segment (AIS) is a unique axonal subdomain responsible for the generation of the neuronal action potential and the maintenance of the axon-dendritic functional polarity. Despite its importance, the mechanisms controlling AIS development and maintenance remain largely unknown. Here we show that the AIS microtubule cytoskeleton is composed of a pool of more stable, detergent resistant, microtubules. This AIS specific characteristic is conferred by the presence of CK2, an important regulator of microtubule stability, in the AIS during its development and maturation. We show that CK2α and CK2α′ subunits concentrate at the AIS from its initial development, at the same time as pIκBα and ankyrinG. CK2 pharmacological inhibition or suppression of CK2α expression with nucleofected interference RNAs modifies microtubule characteristics throughout the neuron, changes KIF5C distribution, and impairs its own concentration at the AIS, as well as that of ankyrinG, ankyrinG-GFP, pIκBα and voltage gated sodium channels. Moreover, CK2α concentration at the AIS depends on IκBα phosphorylation by IKK and ankyrinG. In conclusion, our results demonstrate a mutual dependence of CK2, ankyrinG and pIκBα for their concentration at the axon initial segment, which is related to the specific characteristics of microtubules at the AIS. [ABSTRACT FROM AUTHOR]

Neurons are an extremely diverse group of excitable cells with a wide variety of morphologies including complex dendritic trees and very long axons. The electrical properties of neurons depend not only on the types of ion channels and receptors expressed, but also on where these channels are located in the cell. Two extreme examples that illustrate the subcellular polarized nature of neurons and the tight regulation of ion channel localization can be seen at the axon initial segment and the node of Ranvier. The axon initial segment is important for initiation of action potentials in the axon, whereas the node of Ranvier is required for the rapid, faithful and efficient propagation of action potentials along the axon. Given the similarity of their functions it is not surprising that nearly every protein component of the axon initial segment is also found at the node. However, there is one very important difference between these two sites: nodes require extrinsic, glial-derived factors in order to form, whereas the axon initial segment is intrinsically determined by the neuron. This mini-review discusses recent results that have begun to clarify the intrinsic and extrinsic mechanisms underlying formation of nodes and axon initial segments, and poses several important unanswered questions regarding their unique mechanisms of formation. [ABSTRACT FROM AUTHOR]

Actin waves are filamentous actin (F-actin)-rich structures that initiate in the somato-neuritic area and move toward neurite ends. The upstream cues that initiate actin waves are poorly understood. Here, using an optogenetic approach (Opto-cytTrkB), we found that local activation of the TrkB receptor around the neurite end initiates actin waves and triggers neurite elongation. During actin wave generation, locally activated TrkB signaling in the distal neurite was functionally connected with preferentially localized Rac1 and its signaling pathways in the proximal region. Moreover, TrkB activity changed the location of ankyrinG––the master organizer of the axonal initial segment-and initiated the stimulated neurite to acquire axonal characteristics. Taken together, these findings suggest that local Opto-cytTrkB activation switches the fate from minor to major axonal neurite during neuronal polarization by generating actin waves. • The photoactivatable TrkB receptors initiate actin waves in developing neurons • Activated TrkB generates actin waves through the PI3K/AKT pathway • Activated TrkB at the neurite end mediates Rac1 signaling from the cell body • Local TrkB activation recruits key axonal proteins to the stimulated neurite Actin waves are the drivers to transport axon-promoting factors, yet its upstream regulator remains elusive. Using Opto-cytTrkB system, Woo et al. delineate the role of TrkB signaling on actin waves. They report that axonal molecules relocate to the TrkB-activated neurite, allowing that neurite to acquire an axonal property. [ABSTRACT FROM AUTHOR]

The axon initial segment (AIS) is the site of spike initiation in neurons. Previous studies revealed that spatial distribution of the AIS varies greatly among neurons to meet their specific needs. However, when and how this differentiation arises is unknown. Neurons in the avian nucleus laminaris (NL) are binaural coincidence detectors for sound localization and show differentiation in the distribution of the AIS, with shorter length and a more distal position from the soma with an increase in tuning frequency. We studied these characteristics of the AIS in NL neurons of the chicken during development and found that the AIS differentiates in its distribution after initial formation, and this is driven by activity-dependent and activity-independent mechanisms that differentially regulate distal and proximal boundaries of the AIS. Before hearing onset, the ankyrinG-positive AIS existed at a wide stretch of proximal axon regardless of tuning frequency, but Na+ channels were only partially distributed within the AIS. Shortly after hearing onset, Na+ channels accumulated along the entire AIS, which started shortening and relocating distally to a larger extent in neurons with higher tuning frequencies. Ablation of inner ears abolished the shortening of the AIS without affecting the position of its proximal boundary, indicating that both distal and proximal AIS boundaries are disassembled during development, and the former is dependent on afferent activity. Thus, interaction of these activity-dependent and activity-independent mechanisms determines the cell-specific distribution of the AIS in NL neurons and plays a critical role in establishing the function of sound localization circuit.

Axonal injury and degeneration, whether primary or secondary, contribute to the morbidity and mortality seen in many acquired and inherited central nervous system (CNS) and peripheral nervous system (PNS) disorders, such as traumatic brain injury, spinal cord injury, cerebral ischemia, neurodegenerative diseases, and peripheral neuropathies. The calpain family of proteases has been mechanistically linked to the dysfunction and degeneration of axons. While the direct mechanisms by which transection, mechanical strain, ischemia, or complement activation trigger intra-axonal calpain activity are likely different, the downstream effects of unregulated calpain activity may be similar in seemingly disparate diseases. In this review, a brief examination of axonal structure is followed by a focused overview of the calpain family. Finally, the mechanisms by which calpains may disrupt the axonal cytoskeleton, transport, and specialized domains (axon initial segment, nodes, and terminals) are discussed., (© 2013.)