Axonal Membrane Research Articles

A tale of two methods: Identifying neuronal CB1 receptors.

A paper by Dr. G. Marsicano's group [1] in this issue of Molecular Metabolism is clarifying and further elaborating on some of their previous results on the action of cannabinoid type 1 receptor (CB1) in neuronal mitochondria [2]. This new article was written, at least in part, in response to our finding that anti-CB1 serum used in this as well as in other studies also recognizes mitochondrial stomatin-like protein 2 [3]. Although we did not specifically criticize their major findings and general approach, we did emphasize the possible technical issues that can occur when these antibodies are used. We believe that it is a constructive course of action when different laboratories publicly discuss limitations of methodologies and reliability of the data interpretation in biomedicine. Study of mitochondria in the brain is one of those topics that merit such discourse. “Hard core” mitochondrial bioenergetics has been most extensively studied in tissues with homogenous cell populations, such as the liver, muscle, and heart, that most reliably (albeit not perfectly) provide isolation of mitochondria from the cell type of interest (e.g., hepatocytes and myocytes). The brain, however, consists of multiple cell types and subclasses, and it is virtually impossible to isolate very pure mitochondrial fractions using currently available technologies. In accord, Marsciano and colleagues previously reported that the CB1 agonist, WIN 55,212-2 (WIN), at concentrations of 50 nM and 100 nM, reduced mitochondrial respiration by about 40% and 50%, respectively [2]. In the new study, they report approximately 7% and 20% reduction of mitochondrial respiration at corresponding concentrations of WIN [1]. A confounding factor may be contamination of mitochondrial fractions with the fragments of axonal cell membranes that are known to contain CB1. Hebert-Chatelain et al. [1] also used more sensitive immunoperoxidase cytochemical method with DAB–Ni as a chromogen. They now report mitochondrial labeling in mice of different genotypes, including CB1-KO mice, similar to what we reported. We agree with Dr. Marsicano that adapted experimental procedures and proper controls are essential for correct interpretations of the data. Their and our observations are not too dissimilar; nevertheless, different conclusions may be drawn. We hope that these constructive interactions will increase the drive to improve currently available experimental technologies so that fundamental issues regarding brain mitochondria can be more conclusively addressed in future studies.

Dysregulated expression of lipid storage and membrane dynamics factors in Tia1 knockout mouse nervous tissue

During cell stress, the transcription and translation of immediate early genes are prioritized, while most other messenger RNAs (mRNAs) are stored away in stress granules or degraded in processing bodies (P-bodies). TIA-1 is an mRNA-binding protein that needs to translocate from the nucleus to seed the formation of stress granules in the cytoplasm. Because other stress granule components such as TDP-43, FUS, ATXN2, SMN, MAPT, HNRNPA2B1, and HNRNPA1 are crucial for the motor neuron diseases amyotrophic lateral sclerosis (ALS)/spinal muscular atrophy (SMA) and for the frontotemporal dementia (FTD), here we studied mouse nervous tissue to identify mRNAs with selective dependence on Tia1 deletion. Transcriptome profiling with oligonucleotide microarrays in comparison of spinal cord and cerebellum, together with independent validation in quantitative reverse transcriptase PCR and immunoblots demonstrated several strong and consistent dysregulations. In agreement with previously reported TIA1 knock down effects, cell cycle and apoptosis regulators were affected markedly with expression changes up to +2-fold, exhibiting increased levels for Cdkn1a, Ccnf, and Tprkb vs. decreased levels for Bid and Inca1 transcripts. Novel and surprisingly strong expression alterations were detected for fat storage and membrane trafficking factors, with prominent +3-fold upregulations of Plin4, Wdfy1, Tbc1d24, and Pnpla2 vs. a −2.4-fold downregulation of Cntn4 transcript, encoding an axonal membrane adhesion factor with established haploinsufficiency. In comparison, subtle effects on the RNA processing machinery included up to 1.2-fold upregulations of Dcp1b and Tial1. The effect on lipid dynamics factors is noteworthy, since also the gene deletion of Tardbp (encoding TDP-43) and Atxn2 led to fat metabolism phenotypes in mouse. In conclusion, genetic ablation of the stress granule nucleator TIA-1 has a novel major effect on mRNAs encoding lipid homeostasis factors in the brain, similar to the fasting effect.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-014-0397-x) contains supplementary material, which is available to authorized users.

Identification of transcriptional regulatory elements for Ntng1 and Ntng2 genes in mice

BackgroundHigher brain function is supported by the precise temporal and spatial regulation of thousands of genes. The mechanisms that underlie transcriptional regulation in the brain, however, remain unclear. The Ntng1 and Ntng2 genes, encoding axonal membrane adhesion proteins netrin-G1 and netrin-G2, respectively, are paralogs that have evolved in vertebrates and are expressed in distinct neuronal subsets in a complementary manner. The characteristic expression patterns of these genes provide a part of the foundation of the cortical layer structure in mammals.ResultsWe used gene-targeting techniques, bacterial artificial chromosome (BAC)-aided transgenesis techniques, and in vivo enhancer assays to examine transcriptional mechanisms in vivo to gain insight into how the characteristic expression patterns of these genes are acquired. Analysis of the gene expression patterns in the presence or absence of netrin-G1 and netrin-G2 functional proteins allowed us to exclude the possibility that a feedback or feedforward mechanism mediates their characteristic expression patterns. Findings from the BAC deletion series revealed that widely distributed combinations of cis-regulatory elements determine the differential gene expression patterns of these genes and that major cis-regulatory elements are located in the 85–45 kb upstream region of Ntng2 and in the 75–60 kb upstream region and intronic region of Ntng1. In vivo enhancer assays using 2-kb evolutionarily conserved regions detected enhancer activity in the distal upstream regions of both genes.ConclusionsThe complementary expression patterns of Ntng1 and Ntng2 are determined by transcriptional cis-regulatory elements widely scattered in these loci. The cis-regulatory elements characterized in this study will facilitate the development of novel genetic tools for functionally dissecting neural circuits to better understand vertebrate brain function.

Role of neuronal calcium sensor protein VILIP-1 in synaptic plasticity and neurodegeneration

Calcium signals regulate a wide range of cellular functions including neurotransmission, signal transduction, gene expression, cytoskeleton dynamics, cell metabolism, cell cycle and cell death. Visinin-like protein 1 (VILIP-1) is a neuronal Ca2+ sensor (NCS) protein that belongs to the calmodulin superfamily of calcium sensor proteins. VILIP-1 shows cell surface membrane association, including association with membranes of axons and dendrites, where it functions as a modulator of cell surface associated proteins.

7. Effects of fampridine PR on axonal function in multiple sclerosis

Fampridine PR (prolonged-release 4-aminopyridine tablets) is a treatment for walking disability in multiple sclerosis (MS). While 4-aminopyridine is known to block kV 1.1 potassium channels in vitro, the mechanisms underlying its beneficial effects in the clinical setting have not been investigated. The aim of the present study was to investigate the effects of fampridine on axonal function in an MS cohort. Studies were conducted on 13 MS patients and 29 aged-matched controls. Studies were conducted at baseline and 6 weeks following the commencement of fampridine PR 10 mg b.d. Axonal function was assessed using nerve excitability techniques, which provide information on axonal ion channel function and membrane potential. Neurophysiological parameters were correlated with clinical measures of functional ability, namely hand grip dynamometry, 9-hole peg test, timed 25 foot walk and through questionnaires assessing aspects of upper and lower limb function. There were prominent alterations in nerve excitability parameters noted in baseline recordings in MS patients compared to age-matched controls. Specifically there were reductions in depolarizing threshold electrotonus at 40–60 ms and 90–100 ms ( p = 0.007 and p < 0.001 respectively). These changes were accompanied by reduced superexcitability ( p = 0.002). Following fampridine treatment these abnormalities became less prominent, with mean values approaching the normal range. Significant correlations were also noted between changes in nerve excitability parameters following fampridine treatment and measures of functional performance. Of note, changes in hyperpolarizing threshold electrotonus at the 90–100 ms correlated with changes in hand grip strength ( r = −0.615) and in subjective assessments of lower limb function using the ABILOCO questionnaire ( r = 0.587). The study has demonstrated baseline alterations in nerve excitability parameters in MS patients, which improve following fampridine PR treatment. Furthermore, the study has demonstrated that there are significant correlations between changes in excitability and measures of functional performance and that these are detectable in measures of both upper and lower limb function.

Traumatic brain injury may increase risk of young onset dementia

Traumatic brain injury may increase risk of young onset dementia

2. Insulin pump therapy in type 1 diabetes: Potential to be neuroprotective

Background Diabetic neuropathy is a common complication of diabetes. While strict glycaemic control through multiple daily insulin injections (MDII) or continuous subcutaneous insulin infusion (CSII) may reduce risk of neuropathy development, the potential differences in axonal function between CSII and MDII treated patients have not been evaluated. Objectives To establish if there were differences in axonal function between patients treated with MDII and CSII . Methods A total of 46 type 1 diabetic patients underwent a comprehensive neurological examination to identify the presence of neuropathy. Subsequently, 34 non-neuropathic type 1 diabetic patients were recruited and grouped according to insulin delivery method: MDII ( n = 20, 14M:6F, age 28.37 ± 1.67 yrs) or CSII ( n = 14, 9M:5F, age 27.77 ± 3.26 yrs). Nerve excitability testing, a technique that provides information regarding axonal ion-channel properties, was performed on the median nerve in all patients at baseline and 6–12 months. Groups were matched for age, gender, HbA1c%, BMI and disease duration. Excitability testing was also performed on 20 age-matched healthy controls. Results Subjects demonstrated pronounced alteration in numerous excitability parameters reflecting axonal dysfunction compared to controls. Greater abnormalities in markers of nerve membrane potential were noted in the MDII group compared to controls, including superexcitability ( p p p CSII patients. The differences between the two groups were noted in cross-sectional recordings and at 6–12 month follow-up. Conclusions CSII -treated patients have normal excitability values, in contrast to MDII -treated patients. The abnormalities in the MDII group reflect altered axonal membrane potential. Critically, the differences between the two groups are apparent even in the absence of neuropathy and are maintained at follow-up. These data provide a basis for studies investigating the neuroprotective potential of CSII in type 1 diabetic patients.

β‐Amyloid is transmitted via neuronal connections along axonal membranes

β-amyloid plaque is a critical pathological feature of Alzheimer disease. Pathologic studies suggest that neurodegeneration may occur in a retrograde fashion from axon terminals near β-amyloid plaques, and that plaque may spread through brain regions. However, there is no direct experimental evidence to show transmission of β-amyloid. Microscopic imaging data of β-amyloid transmission was acquired in cortical neuron cultures from Sprague-Dawley rat embryos using polydimethylsiloxane (PDMS) microfluidic culture chambers and in brain sections from in vivo β-amyloid injection. We present direct imaging evidence in cultured cortical neurons, using PDMS microfluidic culture chambers, that β-amyloid is readily absorbed by axonal processes and retrogradely transported to neuronal cell bodies. Transmission of β-amyloid via neuronal connections was also confirmed in mouse brain. β-Amyloid absorbed by distal axons accumulates in axonal swellings, mitochondria, and lysosomes of the cell bodies. Interestingly, dynasore, an inhibitor of dynamin, which is a protein indispensable for endocytosis, did not prevent retrograde transport of β-amyloid, indicating that β-amyloid is absorbed onto axonal membranes and transmitted via them to the cell body. Dynasore did decrease the transneuronal transmission of β-amyloid, suggesting that this requires the internalization and secretion of β-amyloid. Our findings provide direct in vitro and in vivo evidence for spreading of β-amyloid through neuronal connections, and suggest possible therapeutic approaches to blocking this spread.

A compact theory of magnetic nerve stimulation: predicting how to aim.

BackgroundA compact theory that predicts quantitatively when and where magnetic neurostimulation will occur is needed as a guide to therapy, ideally providing a single equation that defines the target volume of tissue excited by single or dual coils.MethodsA first-principles analysis of magnetic stimulation incorporating a simplified description of electromagnetic fields and a simplified cable theory of the axon yields a mathematical synthesis predicting how to aim.ResultsNerve stimulation produced by a single circular coil having one or more closely packed turns occurs in donut shaped volume of tissue beneath the coil. Axons spanning several millimeters are the sites of magnetic stimulation. The sites of maximal transmembrane depolarization in nerve fibers correspond to points where the axons enter or exit this volume of magnetically induced voltage and current. The axonal membrane at one end is depolarized locally during the rising phase of current in the coil. The axonal membrane at the opposite end is depolarized locally during the falling phase of current in the coil. Penetration depths of several centimeters from the skin surface or approximately one to two coil radii are practical. With two coils placed in a figure-of-eight configuration the separate clockwise and counterclockwise currents generate magnetic fields that add, producing maximal stimulation of a spindle shaped volume, centered at a depth of one-third to one-half coil radius from the body surface.ConclusionsThis condensed synthesis of electromagnetic theory and cable theories of axon physiology provides a partial solution to the targeting problem in peripheral and in transcranial magnetic stimulation.

Role of myelin-associated glycoprotein (siglec-4a) in the nervous system.

Myelin-associated glycoprotein (MAG) is a 100 kDa glycoprotein located at the innermost layer of myelin sheets that remains in intimate contact with the axonal membrane. It is selectively expressed by myelinating cells including Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS). Due to its selective location and its effects on neurons, it was originally thought to be involved in axon-glia communication. The generation of MAG-deficient mice greatly expanded our knowledge about the physiological role of MAG, which helped to establish its critical roles in the normal formation and maintenance of myelinated axons. Interest in MAG was revived when it was described as the first myelin-derived inhibitor of axon regeneration. Since then numerous publications have provided detailed information about its axonal receptors and their signaling pathways. Recently, the nurture role of MAG on neurons was confirmed. On the other hand, MAG mediates signals coming from the axons that strongly impact on oligodendrocytes and Schwann cells, highlighting the bidirectional nature of axon-glia communication. Overall, MAG is a critical component of axon-glia interactions with multiple functions in the biology of both neurons and glial cells.

Membrane resealing as a promising strategy for early treatment of neurotrauma

Membrane resealing as a promising strategy for early treatment of neurotrauma

Oxidative phosphorylated neurofilament protein M protects spinal cord against ischemia/reperfusion injury.

Previous studies have shown that neurofilament protein M expression is upregulated in the early stage of spinal cord ischemia/reperfusion injury, indicating that this protein may play a role in the injury process. In the present study, we compared protein expression in spinal cord tissue of rabbits after 25 minutes of ischemia followed by 0, 12, 24, or 48 hours of reperfusion with that of sham operated rabbits, using proteomic two-dimensional gel electrophoresis and mass spectrometry. In addition, the nerve repair-related neurofilament protein M with the unregulated expression was detected with immunohistochemistry and western blot analysis. Two-dimensional gel electrophoresis and mass spectrometry showed that, compared with the sham group, upregulation of protein expression was most significant in the spinal cords of rabbits that had undergone ischemia and 24 hours of reperfusion. Immunohistochemical analysis revealed that neurofilament protein M was located in the membrane and cytoplasm of neuronal soma and axons at each time point after injury. Western blot analysis showed that neurofilament protein M expression increased with reperfusion time until it peaked at 24 hours and returned to baseline level after 48 hours. Furthermore, neurofilament protein M is phosphorylated under oxidative stress, and expression changes were parallel for the phosphorylated and non-phosphorylated forms. Neurofilament protein M plays an important role in spinal cord ischemia/reperfusion injury, and its functions are achieved through oxidative phosphorylation.

High-content imaging of presynaptic assembly

Presynaptic assembly involves the specialization of a patch of axonal membrane into a complex structure that supports synaptic vesicle exocytosis and neurotransmitter release. In mammalian neurons, presynaptic assembly is widely studied in a co-culture assay, where a synaptogenic cue expressed at the surface of a heterologous cell induces presynaptic differentiation in a contacting axon. This assay has led to the discovery of numerous synaptogenic proteins, but has not been used to probe neuronal mechanisms regulating presynaptic induction. The identification of regulatory pathways that fine-tune presynaptic assembly is hindered by the lack of adequate tools to quantitatively image this process. Here, we introduce an image-processing algorithm that identifies presynaptic clusters in mammalian co-cultures and extracts a range of synapse-specific parameters. Using this software, we assessed the intrinsic variability of this synaptic induction assay and probed the effect of eight neuronal microRNAs on presynaptic assembly. Our analysis revealed a novel role for miR-27b in augmenting the density of presynaptic clusters. Our software is applicable to a wide range of synaptic induction protocols (including spontaneous synaptogenesis observed in neuron cultures) and is a valuable tool to determine the subtle impact of disease-associated genes on presynaptic assembly.

Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors

Action potential initiation and conduction along peripheral axons is a dynamic process that displays pronounced activity dependence. In patients with neuropathic pain, differences in the modulation of axonal conduction velocity by activity suggest that this property may provide insight into some of the pathomechanisms. To date, direct recordings of axonal membrane potential have been hampered by the small diameter of the fibers. We have therefore adopted an alternative approach to examine the basis of activity-dependent changes in axonal conduction by constructing a comprehensive mathematical model of human cutaneous C-fibers. Our model reproduced axonal spike propagation at a velocity of 0.69 m/s commensurate with recordings from human C-nociceptors. Activity-dependent slowing (ADS) of axonal propagation velocity was adequately simulated by the model. Interestingly, the property most readily associated with ADS was an increase in the concentration of intra-axonal sodium. This affected the driving potential of sodium currents, thereby producing latency changes comparable to those observed for experimental ADS. The model also adequately reproduced post-action potential excitability changes (i.e., recovery cycles) observed in vivo. We performed a series of control experiments replicating blockade of particular ion channels as well as changing temperature and extracellular ion concentrations. In the absence of direct experimental approaches, the model allows specific hypotheses to be formulated regarding the mechanisms underlying activity-dependent changes in C-fiber conduction. Because ADS might functionally act as a negative feedback to limit trains of nociceptor activity, we envisage that identifying its mechanisms may also direct efforts aimed at alleviating neuronal hyperexcitability in pain patients.

Gas6 Enhances Axonal Ensheathment by MBP+Membranous Processes in Human DRG/OL Promyelinating Co-Cultures

The molecular requirements for human myelination are incompletely defined, and further study is needed to fully understand the cellular mechanisms involved during development and in demyelinating diseases. We have established a human co-culture model to study myelination. Our earlier observations showed that addition of human γ-carboxylated growth-arrest-specific protein 6 (Gas6) to human oligodendrocyte progenitor cell (OPC) cultures enhanced their survival and maturation. Therefore, we explored the effect of Gas6 in co-cultures of enriched OPCs plated on axons of human fetal dorsal root ganglia explant. Gas6 significantly enhanced the number of myelin basic protein-positive (MBP+) oligodendrocytes with membranous processes parallel with and ensheathing axons relative to co-cultures maintained in defined medium only for 14 days. Gas6 did not increase the overall number of MBP+ oligodendrocytes/culture; however, it significantly increased the length of MBP+ oligodendrocyte processes in contact with and wrapping axons. Multiple oligodendrocytes were in contact with a single axon, and several processes from one oligodendrocyte made contact with one or multiple axons. Electron microscopy supported confocal Z-series microscopy demonstrating axonal ensheathment by MBP+ oligodendrocyte membranous processes in Gas6-treated co-cultures. Contacts between the axonal and oligodendrocyte membranes were evident and multiple wraps of oligodendrocyte membrane around the axon were visible supporting a model system in which to study events in human myelination and aspects of non-compact myelin formation.

Pathophysiology of immune‐mediated demyelinating neuropathies—part I: Neuroscience

This first article of this review deals with neuroscientific aspects of immune-mediated demyelinating neuropathies. It describes the anatomy and physiology of normal myelinated axons, methods of studying peripheral nerve physiology, pathophysiological consequences of demyelination or damage at the node of Ranvier, and the mechanisms that may lead to impaired axonal membrane dysfunction or axonal degeneration. This article (part I) will be followed by a second (part II) dealing with clinical aspects of these neuropathies.

Axonal spectrins: All-purpose fences

A membrane barrier important for assembly of the nodes of Ranvier is found at the paranodal junction. This junction is comprised of axonal and glial adhesion molecules linked to the axonal actin–spectrin membrane cytoskeleton through specific adaptors. In this issue, Zhang et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201308116) show that axonal βII spectrin maintains the diffusion barrier at the paranodal junction. Thus, βII spectrin serves to compartmentalize the membrane of myelinated axons at specific locations that are determined either intrinsically (i.e., at the axonal initial segment), or by axoglial contacts (i.e., at the paranodal junction).

Single dose of Glycoprotein K (gK)-deleted HSV-1 live-attenuated virus protects mice against lethal vaginal challenge with HSV-1 and HSV-2 and induces lasting T cell memory immune responses

BackgroundHerpes simplex virus type-1(HSV-1) and HSV-2 are important human pathogens that cause significant ocular and urogenital complications, respectively. We have previously shown that HSV-1 virions lacking glycoprotein K (gK) are unable to enter into neurons via synaptic axonal membranes and be transported in either retrograde or anterograde manner. Here, we tested the ability of HSV-1 (F) gK-null to protect against lethal challenge with either highly virulent ocular HSV-1 (McKrae strain), or genital HSV-2 (G strain). The gK-null virus vaccine efficiently protected mice against lethal vaginal infection with either HSV-1(McKrae) or HSV-2 (G).ResultsFemale mice were immunized via a single intramuscular injection with 106 PFU of the gK-null virus. Immunized mice were treated with Depo-Provera fourteen days after vaccination and were challenged via the vaginal route one week later. Ninety percent of mice vaccinated with the gK-null virus survived HSV-1 (McKrae) challenge, while 70% of these mice survived after HSV-2 (G) challenge. Moreover, all vaccinated mice exhibited substantially reduced disease symptoms irrespective of HSV-1 or HSV-2 challenge as compared to the mock vaccinated challenge group. T-cell memory immune responses to specific glycoprotein B (gB) and glycoprotein D (gD) peptide epitopes were detectable at 7 months post vaccination.ConclusionsThese results suggest that the highly attenuated, non-neurotropic gK-null virus may be used as an effective vaccine to protect against both virulent HSV-1 and HSV-2 genital infections and induce lasting immune responses.

Tryptamine Induces Axonopathy and Mitochondriopathy Mimicking Neurodegenerative Diseases via Tryptophanyl-tRNA Deficiency

Neurodegeneration is induced by tryptamine, a human diet constituent, which easily crosses the blood/brain barrier. Tryptamine neurotoxicity, caused by tryptophanyl-tRNA synthetase (TrpRS) inhibition and downregulation leads to tryptophanyl-tRNA deficiency and synthesis of aberrant proteins. We identified axonal defects in hippocampus of tryptamine- treated mice similar to those observed in human brain of patients with Alzheimer's disease, multiple sclerosis and epilepsy using anti-TrpRS site-directed antibodies. The axonal defects are characterized by swellings that accumulate abnormal amounts of helical filaments and amyloid. Tryptamine produced a decreased density of somatic mitochondria concomitant with neuronal loss in mouse hippocampus. In addition, tryptamine evoked accumulation and clustering of small mitochondria in mouse hippocampus causing axonal swellings. Similarly, mitochondrial fission, fusion and clustering were revealed in human neuronal cells after tryptamine administration. Moreover the tryptamine-induced mitochondrial neuropathology includes electron-dense deposits comprising helical fibrils, cristae disruption, cristolysis, mitochondrial swelling and mitochondria-derived vesicles. TrpRS+ helical filamentous tangles formed in both neuronal and kidney cells following tryptamine treatment suggest a tryptamine broad cytotoxic repertoire in damaging vital organs. Tryptamine elicited vesicularization of inner and outer mitochondrial membranes, axonal and cell membranes. Ultrastructurally, fragmentation of swollen degenerated mitochondria, small mitochondria clustering and neurofibrillary tangles are associated with axonal membrane protrusions attributed as neuritic swellings at a lower magnification. TrpRS+ axonal swellings associated with neuropathology of patients and tryptamine-treated human cells suggest that under toxic concentrations, tryptamine is implicated as a causative agent in neurodegeneration resembling that defining a number of human diseases.

P.8.11 Glatiramer acetate improved motor conduction velocity in dy2J/dy2J mouse peripheral neuropathy

The dy 2J /dy 2J mouse model of laminin α 2-deficient congenital muscular dystrophy (MDC1A) has prominent peripheral neuropathy with slowed conduction. The conduction slowing may be due to reduced myelinated axon number, diameter, and atypical Schwann cell ensheathement/amyelination with aberrant basal lamina, nodal gap shortening, and decreased axon membrane excitability. Although no inflammatory mechanism was identified in dy 2J /dy 2J neuropathy, other genetically mediated neuropathies show low-grade inflammation and immune pathways play a pathological role. The immune modulating agent, Glatiramer acetate (GA) improves dy 2J /dy 2J mouse mobility and hind limb muscle strength, and shows significant beneficial effect in the neuropathy of experimental autoimmune neuritis (EAN). GA mechanisms of action from experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis studies are at various levels of the immune response (skewing T-cells from pro- to anti-inflammatory pathways) and generating neuroprotective activity (brain derived neurotrophic factor BDNF, anti-inflammatory cytokines). Because of GA’s beneficial effect in the dy 2J /dy 2J mouse model we evaluated it’s effect on dy 2J /dy 2J peripheral neuropathy motor conduction. Homozygous dy 2J /dy 2J and control mice were treated with GA or placebo for 12 weeks from 6 weeks of age. Outcome measures included sciatic-posterior tibial motor nerve conduction parameters (NCV, distal latency, and CMAP amplitude, area and dispersion) at 18 weeks. GA treated dy 2J /dy 2J mice showed significantly improved average sciatic-posterior tibial nerve motor conduction velocity 50.35 ± 2.9 m/s versus untreated dy 2J /dy 2J 34.49 ± 2.14 m/s ( p 2 J /dy 2J mouse model of congenital muscular dystrophy.