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At least 19 recordsLinked to original sources
PubMed2005

Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum.

One of the characteristic pathologic changes in classic motor neuron disease (MND) is the presence of ubiquitin-immunoreactive (ub-ir) inclusions in the cytoplasm of lower motor neurons. In addition, cases of MND with dementia (MND-d) also have ub-ir neuronal cytoplasmic inclusions and dystrophic neurites in extramotor neocortex and hippocampus. Although this extramotor pathology is a highly sensitive marker for dementia in MND, similar changes are found in a subset of patients with frontotemporal dementia (FTD) with no motor symptoms (FTD-MND type). The purpose of this study is to more fully describe and compare the pattern of ub-ir pathology in these 3 conditions. We performed ubiquitin immunohistochemistry on postmortem tissue, representing a wide range of neuroanatomic structures, in cases of classic MND (n = 20), MND-d (n = 15), and FTD-MND type (n = 15). We found the variety of morphologies and the anatomic distribution of ub-ir pathology to be greater than previously documented. Moreover, the degree of overlap suggests that MND, MND-d, and FTD-MND type represent a spectrum of clinical disease with a common pathologic substrate. The only finding restricted to a specific subgroup of patients was the presence of ub-ir neuronal intranuclear inclusions in some cases of familial FTD.

Adult↗
PubMed1995

In vivo neurotrophic effects of GDNF on neonatal and adult facial motor neurons.

Motor neurons require neurotrophic factor(s) for their survival during development and for maintenance of function in adulthood. In vivo studies have shown that motor neurons respond to a variety of molecules, including ciliary neurotrophic factor, members of the neurotrophin family, and the insulin growth factor IGF-1 (refs 3-13). Here we investigate the potential motor neuron neurotrophic effects of glial-cell-line-derived neurotrophic factor (GDNF), initially identified as a neurotrophic factor for substantia nigra dopaminergic neurons. We find that GDNF is retrogradely transported, in a receptor-mediated fashion, by spinal cord motor neurons in neonatal rats. Local application of GDNF to the transected facial nerve prevents the massive motor neuron cell death and atrophy that normally follows axotomy in the neonatal period. In adult rats, GDNF administered locally or systemically can markedly attenuate the lesion-induced decrease of choline acetyltransferase immunoreactivity in the facial nucleus. Our data indicate that GDNF has very profound neurotrophic effects in vivo on developing as well as on adult motor neurons, and is the most potent motor neuron trophic factor found so far.

Aging↗
PubMed1987

Distinct neurotrophic factors from skeletal muscle and the central nervous system interact synergistically to support the survival of cultured embryonic spinal motor neurons.

Motor neurons isolated from 6-day-old embryonic chick spinal cords require muscle extract for survival in culture; however, it was found, that some motor neurons, identified by retrograde labeling with rhodamine, will survive in mixed spinal cell cultures in the absence of the extract. The motor neuron survival-promoting activity produced by spinal cells is soluble and differs from the factor present in muscle extract, the two activities acting in a synergistic manner: the spinal cell activity potentiated that of muscle to decrease its ED50 by an order of magnitude, the motor neuronal survival (30%) seen in the presence of both factors being more than the sum of their individual activities. This synergism was shown to be restricted to the action of the spinal cell factor on motor neurons, no effect of the factor being noted with sympathetic neurons. As a series of defined growth and survival factors present in the central nervous system (nerve growth factor, brain-derived neurotrophic factor, acidic and basic fibroblast growth factors) had no effect on motor neuron survival, we conclude that the molecule responsible for the motor neuron survival-promoting activity of the spinal cells is a previously undefined factor.

Animals↗
PubMed2001

Regulation of neurotransmitter vesicles by the homeodomain protein UNC-4 and its transcriptional corepressor UNC-37/groucho in Caenorhabditis elegans cholinergic motor neurons.

Motor neuron function depends on neurotransmitter release from synaptic vesicles (SVs). Here we show that the UNC-4 homeoprotein and its transcriptional corepressor protein UNC-37 regulate SV protein levels in specific Caenorhabditis elegans motor neurons. UNC-4 is expressed in four classes (DA, VA, VC, and SAB) of cholinergic motor neurons. Antibody staining reveals that five different vesicular proteins (UNC-17, choline acetyltransferase, Synaptotagmin, Synaptobrevin, and RAB-3) are substantially reduced in unc-4 and unc-37 mutants in these cells; nonvesicular neuronal proteins (Syntaxin, UNC-18, and UNC-11) are not affected, however. Ultrastructural analysis of VA motor neurons in the mutant unc-4(e120) confirms that SV number in the presynaptic zone is reduced ( approximately 40%) whereas axonal diameter and synaptic morphology are not visibly altered. Because the UNC-4-UNC-37 complex has been shown to mediate transcriptional repression, we propose that these effects are performed via an intermediate gene. Our results are consistent with a model in which this unc-4 target gene ("gene-x") functions at a post-transcriptional level as a negative regulator of SV biogenesis or stability. Experiments with a temperature-sensitive unc-4 mutant show that the adult level of SV proteins strictly depends on unc-4 function during a critical period of motor neuron differentiation. unc-4 activity during this sensitive larval stage is also required for the creation of proper synaptic inputs to VA motor neurons. The temporal correlation of these events may mean that a common unc-4-dependent mechanism controls both the specificity of synaptic inputs as well as the strength of synaptic outputs for these motor neurons.

Animals↗
PubMed2005

Postnatal appearance of 5-HT2A receptors on fast flexor and slow extensor rat motor neurons.

Motor neurons to the slowly contracting extensor soleus muscle in behaving rats begin to fire tonically in the 2nd week after birth. In the adult, tonic firing becomes predominant and appears to arise from plateau potentials under monoaminergic control. In the present work, motor neurons to slowly contracting extensor soleus and rapidly contracting extensor digitorum longus, a physiological flexor muscle, were retrogradely labeled with fluorescent dextran and examined for immunoreactivity to 5-HT(2A) receptors in 1 and 2 week old and adult rats. No reactivity was detected at 1 week. At 2 weeks, reactivity was detected on 67% slowly contracting extensor soleus (16 of 24) and 19% extensor digitorum longus (11 of 57) motor neurons. In the adult, the intensity of staining was higher and the percentage of labeled motor neurons 79 for slowly contracting extensor soleus (34 of 43) and 31 for extensor digitorum longus (11 of 35). On slowly contracting extensor soleus motor neurons, labeling appeared more often on soma and dendrites than on dendrites only, whereas on extensor digitorum longus motor neurons, labeling appeared more often on dendrites only. These results are consistent with the hypothesis that serotonergic innervation contributes to the appearance and subsequent increase in tonic firing of rat slowly contracting extensor soleus motor neurons in postnatal development.

Aging↗
PubMed2002

EphA4 constitutes a population-specific guidance cue for motor neurons.

Motor neurons in the ventral neural tube project axons specifically to their target muscles in the periphery. Although many of the transcription factors that specify motor neuron cell fates have been characterized, less is understood about the mechanisms that guide motor axons to their correct targets. We show that ectopic expression of EphA4 receptor tyrosine kinase alters the trajectories of a specific population of motor axons in the avian hindlimb. Most motor neurons in the medial portion of the lateral motor column (LMC) extend their axons aberrantly in the dorsal nerve trunk at the level of the crural plexus, in the presence of ectopic EphA4. This misrouting of motor axons is not accompanied by alterations in motor neuron identity, settling patterns in the neural tube, or the fasciculation of spinal nerves. However, ectopic EphA4 axons do make errors in pathway selection during sorting in the plexus at the base of the hindlimb. These results suggest that EphA4 in motor neurons acts as a population-specific guidance cue to control the dorsal trajectory of their axons in the hindlimb.

Animals↗
PubMed2005

The calpain inhibitor VI prevents apoptosis of adult motor neurons.

Motor neuron cell death was studied in organotypic cultures of adult spinal cord slices from the mouse. Six hours after excision, many motor neuron nuclei displayed apoptotic features including nuclear and chromatin condensation. At this time point, many motor neurons also exhibited immunoreactivity to calpain II. Both the calpain inhibitor VI and ethyleneglycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) prevented the appearance of apoptotic nuclei whereas the pan caspase inhibitor Z-VAD.fmk had no effect. The results suggest that calpain is required for apoptosis of motor neurons and that this type of apoptosis is independent of caspase activation.

Animals↗
PubMed1999

Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease.

OBJECTIVE: To evaluate the sensitivity of transcranial magnetic stimulation (TMS) to identify upper motor neuron involvement in patients with motor neuron disease. BACKGROUND: Diagnosis of ALS depends on upper and lower motor neuron involvement. Lower motor neuron involvement may be documented with electromyography, whereas definite evidence of upper motor neuron involvement may be elusive. A sensitive, noninvasive test of upper motor neuron function would be useful. METHODS: TMS and clinical assessment in 121 patients with motor neuron disease. RESULTS: TMS revealed evidence of upper motor neuron dysfunction in 84 of 121 (69%) patients, including 30 of 40 (75%) patients with only probable upper motor neuron signs and unsuspected upper motor neuron involvement in 6 of 22 (27%) patients who had purely lower motor neuron syndromes clinically. In selected cases, upper motor neuron involvement identified with TMS was verified in postmortem examination. Increased motor evoked potential threshold was the abnormality observed most frequently and was only weakly related to peripheral compound muscle action potential amplitude. In a subset of 12 patients reexamined after 11+/-6 months, TMS showed progression of abnormalities, including progressive inexcitability of central motor pathways and loss of the normal inhibitory cortical stimulation silent period. CONCLUSIONS: TMS provides a sensitive means for the assessment and monitoring of excitatory and inhibitory upper motor neuron function in motor neuron disease.

Adult↗
PubMed1992

Synaptic connections between nonspiking afferent neurons and motor neurons underlying phase-dependent reflexes in crayfish.

1. This paper analyzes the synaptic connections made by nonspiking afferent neurons of the thoracocoxal muscle receptor organ (TCMRO) with basal limb motor neurons in the crayfish. The T fiber, a dynamically sensitive afferent, monosynaptically excites promotor motor neurons. Evidence suggests that both tonic graded chemical transmission and electrical synaptic transmission may be involved, depending on the motor neuron under consideration. 2. In preparations in the active state (spontaneously producing reciprocal motor patterns), the T fiber also inhibits promotor motor neurons in a phase-dependent manner. This inhibitory pathway is probably indirect, because it involves additional synaptic delay. 3. The statically sensitive S fiber also excites promotor motor neurons, but phase-dependent inhibition of promotor motor neurons by the S fiber was not seen. 4. The T fiber excites a subclass of remotor motor neurons (group 1) by a combination of direct chemical input and electrical input. This connection underlies the positive feedback reflex that excites these remotor motor neurons, in a phase-dependent manner, on stretch of the TCMRO during the active state. In inactive preparations, this connection remains subthreshold. 5. Central synaptic outputs of group 1 remotor motor neurons can also inhibit promotor motor neurons. This pathway may contribute to the phase-dependent reflex inhibition of promotor motor neurons that occurs in the active state.

Afferent Pathways↗
PubMed1997

A Schwann cell mitogen accompanying regeneration of motor neurons.

Motor neurons are the only adult mammalian neurons of the central nervous system to regenerate following injury. This ability is dependent on the environment of the peripheral nerve and an intrinsic capacity of motor neurons for regrowth. We report here the identification, using a technique known as messenger RNA differential display, of an extracellular signalling molecule, previously described as the pancreatic secreted protein Reg-2, that is expressed solely in regenerating and developing rat motor and sensory neurons. Axon-stimulated Schwann cell proliferation is necessary for successful regeneration, and we show that Reg-2 is a potent Schwann cell mitogen in vitro. In vivo, Reg-2 protein is transported along regrowing axons and inhibition of Reg-2 signalling significantly retards the regeneration of Reg-2-containing axons. During development, Reg-2 production by motor and sensory neurons is regulated by contact with peripheral targets. Strong candidates for peripheral factors regulating Reg-2 production are cytokines of the LIF/CNTF family, because Reg-2 is not expressed in developing motor or sensory neurons of mice carrying a targeted disruption of the LIF receptor gene, a common component of the receptor complexes for all of the LIF/CNTF family.

Animals↗
PubMed1998

Neuronal injury increases retrograde axonal transport of the neurotrophins to spinal sensory neurons and motor neurons via multiple receptor mechanisms.

We investigated the retrograde axonal transport of 125I-labeled neurotrophins (NGF, BDNF, NT-3, and NT-4) from the sciatic nerve to dorsal root ganglion (DRG) sensory neurons and spinal motor neurons in normal rats or after neuronal injury. DRG neurons showed increased transport of all neurotrophins following crush injury to the sciatic nerve. This was maximal 1 day after sciatic nerve crush and returned to control levels after 7 days. 125I-BDNF transport from sciatic nerve was elevated with injection either proximal to the lesion or directly into the crush site and after transection of the dorsal roots. All neurotrophin transport was receptor-mediated and consistent with neurotrophin binding to the low-affinity neurotrophin receptor (LNR) or Trk receptors. However, transport of 125I-labeled wheat germ agglutinin also increased 1 day after sciatic nerve crush, showing that increased uptake and transport is a generalized response to injury in DRG sensory neurons. Spinal cord motor neurons also showed increased neurotrophin transport following sciatic nerve injury, although this was maximal after 3 days. The transport of 125I-NGF depended on the expression of LNR by injured motor neurons, as demonstrated by competition experiments with unlabeled neurotrophins. The absence of TrkA in normal motor neurons or after axotomy was confirmed by immunostaining and in situ hybridization. Thus, increased transport of neurotrophic factors after neuronal injury is due to multiple receptor-mediated mechanisms including general increases in axonal transport capacity.

Animals↗
PubMed1991

Motor neurons and motor columns of the anterior spinal cord of salamanders: posthatching development and phylogenetic distribution.

The posthatching development of rostral (1st-4th) spinal motor neurons was studied in ten species of salamanders, using horseradish peroxidase and cobaltic lysine tracing techniques. Development of spinal motor neurons differs among species in association with differences in life history and general developmental patterns (i.e., between species with aquatic larvae versus those with direct development, with or without ontogenetic repatterning). In the plesiomorphic state, represented by species with aquatic larvae, five types of motor neurons are present: (1) large, multipolar neurons, believed to be primary motor neurons; (2) medial, pear-shaped neurons; (3) larger, spindle-shaped neurons, which increase in number during posthatching development; (4) cone-shaped neurons, and (5) bilaterally arborizing neurons (found only at the rostral pole of the first spinal nucleus). Direct-developing desmognathine salamanders have the plesiomorphic set of motor neurons, but appear to lack Mauthner neurons. Direct-developing plethodontine salamanders have cone-shaped, pear-shaped, and spindle-shaped neurons, but lack primary motor neurons and Mauthner neurons. Direct-developing bolitoglossine salamanders, which exhibit both pedomorphosis and ontogenetic repatterning, have only medial, pear-shaped neurons, and lack primary motor neurons, spindle-shaped neurons, cone-shaped and bilaterally arborizing neurons. At all developmental stages in all species studied, pear-shaped neurons are always found in medial positions and spindle-shaped neurons are always found in lateral positions. Spindle-shaped neurons are found more laterally as development proceeds. The medial and lateral motor columns of salamanders and amniotes differ in their connections with peripheral targets (i.e., axial muscles vs. limbs). This implies a lack of homology of neuron types in salamanders and amniotes, which has been obscured by the current terminology.

Animals↗
PubMed1982

Neuromuscular transmission at terminals of sprouted mammalian motor neurones.

Motor nerve sprouting was induced in the tensor fasciae latae muscle of mice by partial denervation produced either by cutting (to prevent reinnervation) or crushing (to allow subsequent reinnervation) spinal nerve L4 unilaterally. The quantum content (m) of endplate potentials recorded intracellularly in vitro in the presence of high-Mg2+ and low-Ca2+ ion concentrations was determined up to 400 days later in non-reinnervated, reinnervated and contralateral control muscles. The muscles were then either fixed and stained with silver and cholinesterase for light microscopy, or fixed and examined in the electron microscope. The average value of m in control muscles increased by 4-5-fold as the animals matured in the 4 months following the operations. The average value of m at terminals of sprouted motor neurones in the absence of reinnervation also increased with time after partial denervation but was always less than the value in the corresponding control muscle. In electron micrographs of muscles following L4 section the nerve terminals closely apposed on average only two-thirds of the proportion of junctional folds apposed to terminals in control muscles. When muscles were reinnervated following L4 crush the average value of m at terminals of sprouted and reinnervating motor neurones equalled and sometimes exceeded m in contralateral control muscles. A proportion of muscle fibres had endplate potentials from reinnervating and sprouted axons, and the silver stain showed that these muscle fibres were innervated at the site of the original endplate. At these endplates the fraction of the total quantum content contributed by presumed sprout terminals fell significantly in the 4 months following L4 crush. It is concluded that: (i) in the absence of reinnervation, sprout terminals grow in size but a significant number never occupy all endplate site available to them; and (ii) in the presence of reinnervation axons terminals share some endplates with sprout terminals and grow at the expense of the sprout terminals which are eventually withdrawn from some shared endplates.

Action Potentials↗
PubMed1997

Rapid development of synaptic connections and plasticity between sensory neurons and motor neurons of Aplysia in cell culture: implications for learning and regulation of synaptic strength.

We describe here the time course of functional synapse formation and of the development of short-term synaptic plasticity at Aplysia sensorimotor synapses in cell culture, as well as the effects of blocking protein synthesis or postsynaptic receptors on the development of synaptic transmission and plasticity. We find that synaptic responses can be elicited in 50% of sensory neuron-motor neuron pairs by 1 h after cell contact and that short-term homosynaptic depression and synaptic augmentation and restoration by the endogenous facilitatory transmitter serotonin are present at the earliest stages of synapse formation. Neither block of protein synthesis with anisomycin nor block of two types of postsynaptic glutamate receptor has any effect on the development of synaptic transmission or synaptic plasticity. The rapidity of synapse formation and maturation and their independence of protein synthesis suggest that changes in the number of functional synapses could contribute to short- and intermediate-term forms of synaptic plasticity and learning.

Animals↗
PubMed1995

Synaptic loss in the proximal axon of anterior horn neurons in motor neuron disease.

This report deals with an ultrastructural investigation of the synapses of the proximal axons of normal-appearing anterior horn neurons of 7 patients with amyotrophic lateral sclerosis (ALS) and 4 patients with motor neuron disease who had no upper motor neuron and corticospinal tract involvement (lower motor neuron disease, LMND). Specimens from 12 age-matched individuals who died of non-neurological diseases served as controls. Proximal axons directly emanating from the normal-appearing neurons were examined: 42 axons were from ALS patients, 43 from LMND patients and 87 from controls. Our results show that the number of synapses on axon hillocks, as well as the lengths of the synaptic contact and of the active zone were reduced in both groups of patients (P < 0.0001), but no significant differences were seen between patients and controls with respect to the synaptic parameters of initial axon segments. There was no overall difference between ALS and LMND patients. These findings suggest that the electrophysiological functions pertaining to integration of electrical inputs into the axon and information transduction on the axon may be greatly impaired in the early stages of motor neuron diseases, and that the observed synaptic alterations may be pathological events, likely to be due to anterior horn neuron degeneration.

Aged↗
PubMed1987

Retrograde transport and differential accumulation of serum proteins in motor neurons: implications for motor neuron diseases.

We found immunocytochemical evidence of serum albumin and immunoglobulin G in motor neurons of rats under physiologic conditions, but not when axoplasmic flow was abolished. The amount of serum proteins was highest in somatic motor neurons of the spinal anterior horn, nucleus ambiguous, and trigeminal motor nucleus; less in hypoglossal and facial neurons; and sparse in preganglionic autonomic, oculomotor, and hypothalamic neurons. Toxic or trophic substances, bound to serum proteins, could also be incorporated into motor neurons. Quantitative differences in accumulation paralleled the selective vulnerability of somatic motor neurons in motor neuron diseases.

Animals↗
PubMed2002

Prevalence of upper motor neuron vs lower motor neuron lesions in complete lower thoracic and lumbar spinal cord injuries.

OBJECTIVE: To determine the incidence and etiology of lower motor neuron (LMN) vs upper motor neuron (UMN) lesions in patients with complete thoracic and lumbar spinal cord injuries (SCI). DESIGN: Retrospective chart review. SETTING: A regional Model Spinal Cord Injury System center. METHODS: A consecutive sample of medical records of patients with lower thoracic and upper lumbar (T7-L3) complete SCI admitted from 1979 through 1996 was systematically reviewed. Of the 306 patients evaluated, 156 subjects met inclusion criteria. The incidence and etiology of LMN vs UMN lesions were determined for the following neurologic levels: T7-T9, T10-T12, L1-L3. Lesions were classified as LMN, UMN, or mixed on the basis of the presence or absence of (1) the bulbocavernosus reflex, (2) lower limb deep tendon reflexes below the neurologic level of injury, and (3) the Babinski sign. RESULTS: The incidences of LMN, UMN, and mixed lesions in the T7-T9, T10-T12, and L1-L3 groups were as follows: T7-T9 group (7.3% LMN, 85.5% UMN, 7.3% mixed), T10-T12 group (57% LMN, 17.7% UMN, 25.3% mixed),L1-L3 group (95.5% LMN, 0.0% UMN, 4.5% mixed). Etiology of injury did not significantly influence the likelihood of a LMN lesion. CONCLUSIONS: One cannot determine the type of lesion (UMN vs LMN) on the basis of the neurological level of injury. A detailed clinical examination, including sacral reflexes, is required. This has important prognostic and therapeutic implications for bowel, bladder, and sexual function, as well as mobility. Distinguishing UMN lesions from LMN lesions is also essential for evaluating new interventions in clinical trials for UMN pathology.

Cohort Studies↗