Myelin Deficiency Research Articles

Synchrotron Infrared Microspectroscopy Detecting the Evolution of Huntington’s Disease Neuropathology and Suggesting Unique Correlates of Dysfunction in White versus Gray Brain Matter

Huntington's disease (HD), caused by a mutation of the corresponding gene encoding the protein huntingtin (htt), is characterized by progressive deterioration of cognitive and motor functions, paralleled by extensive loss of striatal neurons. At the cellular level, pathogenesis involves an early and prolonged period of neuronal dysfunction followed by neuronal death. Understanding the molecular events driving these deleterious processes is critical to the successful development of therapies to slow down or halt the progression of the disease. Here, we examined biochemical processes in a HD ex vivo rat model, as well as in a HD model for cultured neurons using synchrotron-assisted Fourier transform infrared microspectroscopy (S-FTIRM). The model, based on lentiviral-mediated delivery of a fragment of the HD gene, expresses a mutant htt fragment in one brain hemisphere and a wild-type htt fragment in the control hemisphere. S-FTIRM allowed for high spatial resolution and distinction between spectral features occurring in gray and white matter. We measured a higher content of β-sheet protein in the striatal gray matter exposed to mutant htt as early as 4 weeks following the initiation of mutant htt exposure. In contrast, white matter tracts did not exhibit any changes in protein structure but surprisingly showed reduced content of unsaturated lipids and a significant increase in spectral features associated with phosphorylation. The former is reminiscent of changes consistent with a myelination deficiency, while the latter is characteristic of early pro-apoptotic events. These findings point to the utility of the label-free FTIRM method to follow mutant htt's β-sheet-rich transformation in striatal neurons ex vivo, provide further evidence for mutant htt amyloidogenesis in vivo, and demonstrate novel chemical features indicative of white matter changes in HD. Parallel studies in cultured neurons expressing the same htt fragments showed similar changes.

Peroxisome-Proliferator-Activated Receptor Gamma Coactivator 1 Contributes to Dysmyelination in Experimental Models of Huntington's Disease

The peroxisome-proliferator-activated receptor gamma coactivator 1 α (PGC1α) has been implicated in the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Recent data demonstrating white matter abnormalities in PGC1α knock-out (KO) mice prompted us to examine the role of PGC1α in CNS myelination and its relevance to HD pathogenesis. We found deficient postnatal myelination in the striatum of PGC1α KO mice, accompanied by a decrease in myelin basic protein (MBP). In addition, brain cholesterol, its precursors, and the rate-limiting enzymes for cholesterol synthesis, HMG CoA synthase (HMGCS1) and HMG CoA reductase (HMGCR), were also reduced in PGC1α KO mice. Moreover, knockdown of PGC1α in oligodendrocytes by lentiviral shRNA led to a decrease in MBP, HMGCS1, and Hmgcr mRNAs. Chromatin immunoprecipitations revealed the recruitment of PGC1α to MBP promoter in mouse brain, and PGC1α over-expression increased MBP and SREBP-2 promoter activity, suggesting that PGC1α regulates MBP and cholesterol synthesis at the transcriptional level. Importantly, expression of mutant huntingtin (Htt) in primary oligodendrocytes resulted in decreased expression of PGC1α and its targets HmgcS1, Hmgcr, and MBP. Decreased expression of MBP and deficient myelination were found postnatally and in adult R6/2 mouse model of HD. Diffusion tensor imaging detected white matter abnormalities in the corpus callosum of R6/2 mice, and electron microscopy revealed thinner myelin sheaths and increased myelin periodicity in BACHD [bacterial artificial chromosome (BAC)-mediated transgenic model for Huntington's disease] mice expressing full-length mutant Htt. Together, these data suggest that PGC1α plays a role in postnatal myelination and that deficient PGC1α activity in oligodendrocytes may contribute to abnormal myelination in HD.

Peripheral Nervous System Progenitors Can Be Reprogrammed to Produce Myelinating Oligodendrocytes and Repair Brain Lesions

Neural crest stem cells (NCSCs) give rise to the neurons and glia of the peripheral nervous system (PNS). NCSC-like cells can be isolated from multiple peripheral organs and maintained in neurosphere culture. Combining in vitro culture and transplantation, we show that expanded embryonic NCSC-like cells lose PNS traits and are reprogrammed to generate CNS cell types. When transplanted into the embryonic or adult mouse CNS, they differentiate predominantly into cells of the oligodendrocyte lineage without any signs of tumor formation. NCSC-derived oligodendrocytes generate CNS myelin and contribute to the repair of the myelin deficiency in shiverer mice. These results demonstrate a reprogramming of PNS progenitors to CNS fates without genetic modification and imply that PNS cells could be a potential source for cell-based CNS therapy.

Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex

Mendelian disorders that affect cognition provide a unique opportunity to study the mechanisms of neurodevelopmental disorders through the examination of genetic defects in animals and development of hypotheses that can be tested in human beings. Tuberous sclerosis complex (TSC) is a genetic disease that presents with epilepsy, autism, and intellectual disability. Here we review recent advances in our understanding of TSC pathogenesis and signaling pathways that may be modulated to treat the neurological symptoms. Accumulating evidence suggests that TSC patients have nontuber abnormalities that contribute to the development of the neurological phenotype- in particular, disorganization of axon tracts and deficient myelination. TSC mouse models have failed to replicate the human neuropathology entirely, but have shed light on the cellular abnormalities and the neurobehavioral phenotypes. Most importantly, cell culture and animal models have identified the mTORC1 pathway as a therapeutic target in this disease. Preclinical data strongly suggest that TSC is a disease of abnormal neuronal connectivity. The high incidence of neurodevelopmental deficits, early detection of the disease in very young ages, and availability of mTORC1 inhibitors make TSC a model for other Mendelian disorders of neurocognition and an avenue for the mechanism-based treatment trials of neurodevelopmental disorders.

HDAC-mediated deacetylation of NF-κB is critical for Schwann cell myelination

Schwann cell myelination is tightly regulated by timely expression of key transcriptional regulators that respond to specific environmental cues, yet molecular mechanisms underlying such a process are poorly understood. Here, we report that HDAC1/2-regulated acetylation state of NF-κB is critical in orchestrating the myelination program. Mice lacking HDAC1/2 exhibit severe dysmyelination with Schwann cell development arrested at the immature stage. We find that NF-κB p65 becomes heavily acetylated in HDAC1/2 mutants, inhibiting the expression of positive regulators of myelination, while inducing the expression of differentiation inhibitors. We observe that NF-κB protein complex switches its association with p300 to that with HDAC1/2 as Schwann cells differentiate. NF-κB and HDAC1/2 act coordinately to regulate the transcriptionally-linked chromatin state for Schwann cell myelination. Thus, our results reveal an HDAC-mediated developmental switch for controlling myelination in the peripheral nervous system.

Myelin copper and the cuprizone model of schizophrenia

In recent years increasing evidence is pointing toward white matter abnormalities in schizophrenia and other psychiatric disorders. The present paper will provide an overview over the role of myelin in cognition and brain function, and its potential involvement in brain disorders. Furthermore, we will examine one particular experimental model for the study of dysmyelination, created by the administration of the toxin cuprizone. Cuprizone, a copper chelator, causes white matter abnormalities in rodents. The administration of cuprizone during specific developmental periods allows for the targeting of specific brain areas for dysmyelination. Thus, cuprizone can be used to study the pathogenesis and pathophysiology of myelin deficiencies in the central nervous system, and its effect on behaviors relevant to psychiatric disorders.

Hypomyelination in three Weimaraner dogs

Hypomyelination syndrome of the Weimaraner dog is a disease characterised by a reduction or absence of myelin in the axons of the central nervous system (CNS) exclusively. The objective of this study was to analyse the cause of this deficiency of myelin. Tissue samples of the CNS of three Weimaraner dogs with neurological signs were fixed in 10% formalin and embedded in paraffin wax, and histochemical, immunohistochemical and ultrastructural studies were performed. Histochemical staining with haematoxylin and eosin and Kluver-Barrera techniques showed generalised pallor in the peripheral areas of the ventral and lateral funiculi of the spinal cord. Immunohistochemical analysis showed a weak expression of both proteolipid protein (PLP) and myelin basic protein (MBP) and a marked decrease of Olig2(+) cells in the demyelinated areas. The immunohistochemical findings suggested a myelination or remyelination failure because of the smaller population of oligodendrocytes. However, PLP gene mutations may also be the cause of the decrease of PLP expression as described in other species.

The NIH's Collins Presents Declaration Outlining Impact of hESC Research Ban

In the wake of a district judge's decision on August 23, 2010, to block the use of federal funds for human embryonic stem cell research (hESC), the Obama administration on August 31, 2010, formally challenged the court order and filed notice of plans to appeal the decision to the U.S. Court of Appeals. “The government is seeking a stay of the court's injunction to prevent the irreparable harm and financial harm that could occur if these lifesaving research projects are forced to abruptly shut down,” Justice Department spokesperson Tracy Schmaler said in a statement. “The great potential for significant additional medical breakthroughs is at risk if this research is halted pending the appeals process.” The director of the National Institutes of Health (NIH), Dr. Francis Collins, delivered a separate 12-page declaration to the federal court about the importance of hESC research and the harm that will come from Judge Royce Lamberth's stem cell decision. He pointed out that since the first awards in 2002, the NIH has a total aggregated investment of $546 million in intramural and extramural hESC research. “As a result of these investments, NIH funded animal studies, often referred to as preclinical studies, are underway to test whether these cells or tissues derived from embryonic stem cells, human and/or mouse, are of benefit for retinal degeneration, stroke, liver failure, muscular dystrophy, myelin deficiencies, motor neuron disease and Huntington's disease.” Collins added that the first clinical trial of hESC-derived therapy has received US Food and Drug Administration (FDA) approval to begin enrolling spinal cord injury patients. “This is a remarkable achievement and heralds what should be the beginning of a new era in cell-based therapy. “Equally important, differentiated cells derived from hESC are already successfully being used to develop new therapeutic drugs for a number of diseases including amyotrophic lateral sclerosis (‘Lou Gehrig’s disease') and spinal muscular atrophy, to name just a few. Without dependable and consistent support from NIH, hESC research and development will be dealt a critical blow that will have dire ramifications for those suffering from many diseases and disorders [that] may be treatable with hESC-based therapies or drugs developed using hESC testing.” The declaration also considers the impact of the court's order on the disruption to intramural and extramural research and disruption to the agency's administration and mission. See: http://www.scribd.com/doc/36697386/Final-Collins-Declaration-Aug-31-2010.

Long-term cognitive impairment and myelination deficiency in a rat model of perinatal hypoxic-ischemic brain injury

Although periventricular white matter injury is a leading cause of major neurologic disability in premature infants, the relationship between myelination deficiency and long-term cognitive dysfunction is not well understood. The purpose of this study was to investigate oligodendrocytes myelination and long-term spatial cognitive function in rats with perinatal hypoxia-ischemia (HI). Postnatal day 3 (P3) rats were subjected to right carotid artery ligation followed by 2.5 h of hypoxia (6% oxygen). Brain injury during the early and late phases was evaluated by immunostaining at P6 (72 h after the injury) and P47. Spatial cognitive function was evaluated at P42 using the Morris Water Maze test followed by histologic evaluation. HI caused an increase in pre-oligodendrocytes, astrocytes, and microglia in the ipsilateral white matter 72 h after the insult compared to contralateral regions and sham-operated controls (both p < 0.05). There were significant decreases in myelin basic protein (MBP)and 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase)-labeled oligodendrocytes with glial fibrillary acidic protein (GFAP)-labeled glial scarring in the ipsilateral periventricular white matter at P47 compared to contralateral regions and sham-operated controls (all p < 0.05). The rats with HI had spatial learning deficits in navigation trials (longer escape latency and swimming distance) and memory dysfunction in probe trials (fewer number of platform crossings and percentage of time in the target quadrant) compared with sham-operated controls ( p < 0.05). In this neonatal rat model of HI, myelination deficiency induced by activated astrocytes and microglia during the early phase with subsequent glial scarring was associated with long-term spatial learning and memory dysfunction.

Neuronal expression of the proteolipid protein gene in the medulla of the mouse

The proteolipid protein (PLP) gene (Plp) encodes the major myelin proteins, PLP and DM20. Expression of Plp occurs predominantly in oligodendrocytes, but evidence is accumulating that this gene is also expressed in neurons. In earlier studies, we demonstrated that myelin-deficient (MD) rats, which carry a mutation in the Plp gene, exhibit lethal hypoxic ventilatory depression. Furthermore, we found that, in the MD rat, PLP accumulated in neuronal cell bodies in the medulla oblongata. In the current study, we sought to determine which neurons expressed the Plp gene in the medulla oblongata and whether Plp gene expression changed in neurons with maturation. A transgenic mouse expressing the Plp promoter driving expression of enhanced green fluorescent protein (Plp-EGFP) was used to identify neurons expressing this gene. Plp expression in neurons was confirmed by immunostaining EGFP-positive cells for NeuN and by in situ hybridization for PLP mRNA. The numbers of neurons expressing Plp-EGFP and their distribution increased between P5 and P10 in the medulla. Immunostaining for surface receptors and classes of neurons expressing Plp-EGFP revealed that Plp gene expression in brainstem neurons was restricted to neurons expressing specific ligand-gated channels and biosynthetic enzymes, including glutamatergic NMDA receptors, GABA(A) receptors, and ChAT in defined areas of the medulla. Plp gene expression was rarely found in interneurons expressing GABA and was never found in AMPA receptor- or tyrosine hydroxylase-expressing neurons. Thus, Plp expression in the mouse caudal medulla was found to be developmentally regulated and restricted to specific groups of neurons.

Anatomie fonctionnelle du nerf facial

Embryologic individualization of the facial nerve primordium occurs early and emphasizes trigeminofacial connections and variations in the transitional zone (TZ). In the brainstem, the specific nuclei of the facial nerve are located within five columns corresponding to the main functions. Three-quarters of the fibers are of the special visceral efferent group (SVE). Central connections of the facial motonucleus are numerous, particularly with the trigeminal complex but also the cochlear nerves. Only endoneurium surrounds facial nerve fibers in the cerebellopontine angle; central nervous system tissue offers a small extracellular space, lacking collagen and funicular plexus, without epiperineurium: nerve fibers are therefore more susceptible to injury. The segment of a nerve that reveals both CNS and PNS components is referred to as the transition zone. It should be regarded as a "locus minor resistae" because of poor vascularization and CNS myelin deficiency. The acousticofacial reflex is often absent in patients with hemifacial spasm. Early (R1) and late (R2) responses of the trigeminofacial reflex (blink reflex) in patients with hemifacial spasm are of major interest in understanding both peripheral and central mechanisms.

Alterations of myelin‐specific proteins and sphingolipids characterize the brains of acid sphingomyelinase‐deficient mice, an animal model of Niemann–Pick disease type A

Niemann-Pick disease (NPD) type A is a neurodegenerative disorder caused by sphingomyelin (SM) accumulation in lysosomes relying on reduced or absent acid sphingomyelinase (ASM) activity. NPD-A patients develop progressive neurodegeneration including cerebral and cerebellar atrophy, relevant Purkinje cell and myelin deficiency with death within 3 years. ASM'knock-out' (ASMKO) mice, an animal model of NPD-A, develop a phenotype largely mimicking that of NPD-A. The mechanisms underlying myelin formation are poorly documented in ASMKO mice. In this study we determined the content of four myelin-specific proteins, myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), myelin associated glycoprotein (MAG) and proteolipid protein (PLP), and that of myelin-enriched sphingolipids in the brains of ASMKO and wild-type mice in early stages of post-natal (pn) life. Protein and mRNA analysis revealed that in ASMKO mice beginning from 4 post-natal weeks (wk-pn), the expression levels of MAG, CNP, and MBP were below those observed in wild-type mice and the same applied to PLP at 10 wk-pn. Moreover, at 4 wk-pn the expression of SOX10, one of the transcription factors involved in oligodendrocyte development and maintenance was lower in ASMKO mice. Lipid analysis showed that SM and the gangliosides GM3 and GM2 accumulated in the brains of ASMKO mice, as opposed to galactocerebroside and galactosulfocerebroside that, in parallel with the mRNAs of UDP-galactose ceramide galactosyltransferase and galactose-3-O-sulfotransferase 1, the two transferases involved in their synthesis, decreased. Myelin lipid analysis showed a progressive sphingomyelin accumulation in ASMKO mice; noteworthy, of the two sphingomyelin species known to be resolved by TLC, only that with the lower Rf accumulated. The immunohistochemical analysis showed that the reduced expression of myelin specific proteins in ASMKO mice at 10 wk-pn was not restricted to the Purkinje layer of the cerebellar cortex but involved the cerebral cortex as well. In conclusion, reduced oligodendrocyte metabolic activity is likely to be the chief cause of myelin deficiency in ASMKO mice, thus shedding light on the molecular dysfunctions underlying neurodegeneration in NPD-A.

Linking white and grey matter in schizophrenia: oligodendrocyte and neuron pathology in the prefrontal cortex.

Neuronal circuitry relies to a large extent on the presence of functional myelin produced in the brain by oligodendrocytes. Schizophrenia has been proposed to arise partly from altered brain connectivity. Brain imaging and neuropathologic studies have revealed changes in white matter and reduction in myelin content in patients with schizophrenia. In particular, alterations in the directionality and alignment of axons have been documented in schizophrenia. Moreover, the expression levels of several myelin-related genes are decreased in postmortem brains obtained from patients with schizophrenia. These findings have led to the formulation of the oligodendrocyte/myelin dysfunction hypothesis of schizophrenia. In this review, we present a brief overview of the neuropathologic findings obtained on white matter and oligodendrocyte status observed in schizophrenia patients, and relate these changes to the processes of brain maturation and myelination. We also review recent data on oligodendrocyte/myelin genes, and present some recent mouse models of myelin deficiencies. The use of transgenic and mutant animal models offers a unique opportunity to analyze oligodendrocyte and neuronal changes that may have a clinical impact. Lastly, we present some recent morphological findings supporting possible causal involvement of white and grey matter abnormalities, in the aim of determining the morphologic characteristics of the circuits whose alteration leads to the cortical dysfunction that possibly underlies the pathogenesis of schizophrenia.

MRI detects therapeutic effects in weanling Niemann‐Pick type C mice

To noninvasively evaluate the early effects of Niemann-Pick type C (NPC) disease, diffusion tensor imaging (DTI) was carried out in the brains of very young (23-day-old) mice. The diffusion of water in white matter tracts of Npc1(-/-) mice at this young age was already abnormal, exhibiting decreased anisotropy, as quantified by fractional anisotropy (FA), compared with their wild-type littermates, the controls. Postmortem histological staining revealed myelin deficiencies in Npc1(-/-) mice, consistent with the reduction in FA measured in vivo. Beneficial effects of treatment with allopregnanolone and/or 2 hydroxypropyl-beta-cyclodextrin was also detectable at this age by FA, which correlated with increased myelination as seen by histology. This is the earliest detection of a therapeutic effect in Npc1(-/-) mice.

Epileptic seizures and hippocampal damage after cuprizone-induced demyelination in C57BL/6 mice

Epileptic seizures are known to occur in different animal models of demyelination and have also been described in demyelinating diseases of the central nervous system (CNS) such as multiple sclerosis. How myelin deficiency might cause seizures is unknown, but may involve axonal pathology and resultant alterations in neuronal excitability. The cause of seizures occurring in rodent demyelination models is unknown. In the present study, we used EEG/video monitoring to record seizures occurring during chronic demyelination of C57BL/6 mice fed for 12 weeks with 0.2% cuprizone. Furthermore, in the search for a morphological correlate of the seizures, the hippocampal formation was examined histologically. Epileptiform spikes resembling interictal spikes known from chronic epilepsy were recorded in all cuprizone-treated mice, but not in controls. Most cuprizone-treated animals exhibited generalized tonic–clonic seizures upon stress-inducing stimuli. In addition to the known demyelination of the corpus callosum, massive demyelination was found in the hippocampal formation. This was associated with neuronal alterations, including a loss of neurons in the hilus of the dentate gyrus. In view of the role of the dentate gyrus in epileptogenesis, demyelination leading to axonal pathology and thus neuronal damage as observed in the hilus may be causally involved in the paroxysmal alterations observed after prolonged treatment with cuprizone. The present data suggest a potential role of the hippocampal formation for seizures occurring as a consequence of neuronal damage secondary to CNS demyelination.

Hypomyelination and Congenital Cataract: Neuroimaging Features of a Novel Inherited White Matter Disorder

Hypomyelination and congenital cataract (HCC) is an autosomal recessive white matter disease caused by deficiency of hyccin, a membrane protein implicated in both central and peripheral myelination. We aimed to describe the neuroimaging features of this novel entity. A systematic analysis of patients with unclassified leukoencephalopathies admitted to our institutions revealed 10 children with congenital cataract, slowly progressive neurologic impairment, and diffuse white matter abnormalities on neuroimaging. Psychomotor developmental delay was evident after the first year of life. Peripheral neuropathy was demonstrated by neurophysiologic studies in 9 children. The available neuroimaging studies were retrospectively reviewed. In all patients, neuroimaging revealed diffuse involvement of the supratentorial white matter associated with preservation of both cortical and deep gray matter structures. Supratentorial white matter hypomyelination was detected in all patients; 7 patients also had evidence of variably extensive areas of increased white matter water content. Deep cerebellar white matter hypomyelination was found in 6 patients. Older patients had evidence of white matter bulk loss and gliosis. Proton MR spectroscopy showed variable findings, depending on the stage of the disease. Sural nerve biopsy revealed hypomyelinated nerve fibers. Mutations in the DRCTNNB1A gene on chromosome 7p15.3, causing complete or severe deficiency of hyccin, were demonstrated in all patients. HCC is characterized by a combined pattern of primary myelin deficiency and secondary neurodegenerative changes. In the proper clinical setting, recognition of suggestive neuroimaging findings should prompt appropriate genetic investigations.

Hypomyelination with atrophy of the basal ganglia and cerebellum

Hypomyelination with atrophy of the basal ganglia and cerebellum is a recently defined disorder. Only a few patients have been described. We report on 11 additional patients and new MRI findings and provide histopathologic confirmation of the MRI interpretation. We reviewed the patients' clinical history and present findings. We scored the MRI abnormalities. The histopathology of one patient was re-examined. The patients' early psychomotor development was normal or delayed, followed by increasing extrapyramidal movement abnormalities, ataxia, and spasticity. Mental capacities were variably affected. MRI showed hypomyelination with, on follow-up, evidence of further myelin loss and variable white matter atrophy. The putamen was small or, more often, absent; the head of the caudate nucleus was decreased in size. In contrast, the thalamus and globus pallidus remained normal. Cerebellar atrophy was invariably present. Histopathology confirmed the myelin deficiency, probably related to both lack of deposition and low-grade further loss. The degeneration of putamen was subtotal. The cerebellar cortex was affected, particularly the granular layer. Hypomyelination with atrophy of the basal ganglia and cerebellum is a syndrome diagnosed by distinctive MRI findings. Histopathology confirms hypomyelination, low-grade further myelin loss, subtotal degeneration of the putamen, and cerebellar cortical atrophy. All known patients are sporadic, and the mode of inheritance is unclear.

Myelination of Congenitally Dysmyelinated Spinal Cord Axons by Adult Neural Precursor Cells Results in Formation of Nodes of Ranvier and Improved Axonal Conduction

Emerging evidence suggests that cell-based remyelination strategies may be a feasible therapeutic approach for CNS diseases characterized by myelin deficiency as a result of trauma, congenital anomalies, or diseases. Although experimental demyelination models targeted at the transient elimination of oligodendrocytes have suggested that transplantation-based remyelination can partially restore axonal molecular structure and function, it is not clear whether such therapeutic approaches can be used to achieve functional remyelination in models associated with long-term, irreversible myelin deficiency. In this study, we transplanted adult neural precursor cells (aNPCs) from the brain of adult transgenic mice into the spinal cords of adult Shiverer (shi/shi) mice, which lack compact CNS myelin. Six weeks after transplantation, the transplanted aNPCs expressed oligodendrocyte markers, including MBP, migrated extensively along the white matter tracts of the spinal cord, and formed compact myelin. Conventional and three-dimensional confocal and electron microscopy revealed axonal ensheathment, establishment of paranodal junctional complexes leading to de novo formation of nodes of Ranvier, and partial reconstruction of the juxtaparanodal and paranodal molecular regions of axons based on Kv1.2 and Caspr (contactin-associated protein) expression by the transplanted aNPCs. Electrophysiological recordings revealed improved axonal conduction along the transplanted segments of spinal cords. We conclude that myelination of congenitally dysmyelinated adult CNS axons by grafted aNPCs results in the formation of compact myelin, reconstruction of nodes of Ranvier, and enhanced axonal conduction. These data suggest the therapeutic potential of aNPCs to promote functionally significant myelination in CNS disorders characterized by longstanding myelin deficiency.

CNS Hypomyelination in Rat Terrier Dogs with Congenital Goiter and a Mutation in the Thyroid Peroxidase Gene

Arrested physical development and neurologic abnormalities were identified in 3 of 5 Rat Terrier puppies at 9 weeks of age. Bilaterally firm symmetrical masses were palpated in the region of the thyroid glands. Low serum total (T4) and free thyroxine (FT4, by equilibrium dialysis) and markedly elevated thyroid stimulating hormone (TSH) concentrations supported the diagnosis of hypothyroidism. At necropsy, the thyroid gland was grossly enlarged and histologically exhibited severe, diffuse hyperplasia of the follicular epithelium. Gross examination of the central nervous system revealed a myelin deficiency, most evident in the corpus callosum. Regional distribution of hypomyelination was confirmed histologically, affecting the corpus callosum and, to a lesser degree, the corona radiata, the longitudinal fibers of the pons, the pyramids, and the lateral funiculi of the spinal cord. Myelin reduction was paralleled by axon reduction, suggesting that hypomyelination was a consequence of reduced axonal formation. A homozygous nonsense mutation in the thyroid peroxidase gene was identified in the affected puppies. The dam and a clinically normal litter mate were heterozygous for this mutation, confirming simple autosomal recessive inheritance of the disease trait. The same mutation, causing congenital hypothyroidism with a goiter was previously described in the Toy Fox Terrier breed. Given the ongoing practice of introducing the Toy Fox Terrier genetic background into some Rat Terrier breeding programs to obtain a smaller stature and the apparent relative incidence of the disorder in the 2 breeds, it is likely that this mutation crossed into the Rat Terrier breed from Toy Fox Terriers fairly recently.

Anterograde labeling of the corticospinal tract in jimpy mutant mice by Di I injection into the motor cortex

Carbocyanine fluorescent dye, DiI, is an excellent anterograde/retrograde neural tracer, but its efficacy for the anterograde labeling of neural circuits in the adult brain tends to decrease with ages. The present study shows that an injection of DiI into the motor cortex of the young adult jimpy mutant mice (Plp1(jp)/+) resulted in successful anterograde labeling of corticospinal tract fibers. Furthermore, an injection of Fast Blue into the lumbar spinal cord of the mutant mice resulted in retrograde labeling of layer 5 corticospinal tract neurons within the motor cortex. Since no abnormality except for myelin deficiency is known in the long descending and ascending tracts of jimpy mutant mouse, this mutant is suitable for neural tracing studies of long axonal trajectories with the use of carbocyanine dye, DiI, although these males die between 20 and 40 days of age.