Selective Loss Of Motor Neurons Research Articles

Loss of metabotropic glutamate receptor‐mediated regulation of glutamate transport in chemically activated astrocytes in a rat model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurones accompanied by intense gliosis in lesioned areas of the brain and spinal cord. Glutamate-mediated excitotoxicity resulting from impaired astroglial uptake constitutes one of the current pathophysiological hypotheses explaining the progression of the disease. In this study, we examined the regulation of glutamate transporters by type 5 metabotropic glutamate receptor (mGluR5) in activated astrocytes derived from transgenic rats carrying an ALS-related mutated human superoxide dismutase 1 (hSOD1(G93A)) transgene. Cells from transgenic animals and wild-type littermates showed similar expression of glutamate-aspartate transporter and glutamate transporter 1 (GLT-1) after in vitro activation, whereas cells carrying the hSOD1 mutation showed a three-fold higher expression of functional mGluR5, as observed in the spinal cord of end-stage animals. In cells from wild-type animals, (S)-3,5-dihydroxyphenylglycine (DHPG) caused an immediate protein kinase C (PKC)-dependent up-regulation of aspartate uptake that reflected the activation of GLT-1. Although this effect was mimicked in both cultures by direct activation of PKC using phorbol myristate acetate, DHPG failed to up-regulate aspartate uptake in cells derived from the transgenic rats. The failure of activated mGluR5 to increase glutamate uptake in astrocytes derived from this animal model of ALS supports the theory of glutamate excitotoxicity in the pathogenesis of the disease.

Development of a rat model of amyotrophic lateral sclerosis expressing a human SOD1 transgene

Mutations in copper-zinc superoxide dismutase gene (SOD1) have been linked to some familial cases of ALS. We report here that rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. By comparing the two transgenic rats with different SOD1 mutations, we demonstrate that the time course in these rats was similar to human SOD1-mediated familial ALS. As in the human disease and transgenic ALS mice, pathological analysis shows selective loss of motor neurons in the spinal cords of these transgenic rats. In addition, typical neuronal Lewy body-like hyaline inclusions as well as astrocytic hyaline inclusions identical to those in human familial ALS are observed in the spinal cords. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies).

Loss ofALS2Function Is Insufficient to Trigger Motor Neuron Degeneration in Knock-Out Mice But Predisposes Neurons to Oxidative Stress

Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is caused by a selective loss of motor neurons in the CNS. Mutations in the ALS2 gene have been linked to one form of autosomal recessive juvenile onset ALS (ALS2). To investigate the pathogenic mechanisms of ALS2, we generated ALS2 knock-out (ALS2(-/-)) mice. Although ALS2(-/-) mice lacked obvious developmental abnormalities, they exhibited age-dependent deficits in motor coordination and motor learning. Moreover, ALS2(-/-) mice showed a higher anxiety response in the open-field and elevated plus-maze tasks. Although they failed to recapitulate clinical or neuropathological phenotypes consistent with motor neuron disease by 20 months of age, ALS2(-/-) mice or primary cultured neurons derived from these mice were more susceptible to oxidative stress compared with wild-type controls. These observations suggest that loss of ALS2 function is insufficient to cause major motor deficits or motor neuron degeneration in a mouse model but predisposes neurons to oxidative stress.

ALS‐IgG‐induced selective motor neurone apoptosis in rat mixed primary spinal cord cultures

There is evidence that in sporadic amyotrophic lateral sclerosis (ALS) immunological mechanisms may be involved in the pathophysiology of the disease. We tested whether purified IgG from ALS patients induce cell death in rat mixed primary spinal cord cultures and compared this with the effect of IgG purified from patients with Guillain-Barré syndrome (GBS) or from healthy donors. Treatment with ALS-IgG increases caspase-3 apoptosis when compared with control IgG or with GBS-IgG, but does not induce death by necrosis. Because ALS is characterized by the selective loss of motor neurones, we next assessed the differential effect of ALS-IgG on motor neurones or astrocytes. We showed, semiquantitatively, that motor neurones are more susceptible to apoptosis when cultures were treated with ALS-IgG compared with control-IgG. In conclusion, we have demonstrated in primary spinal cord cultures that IgG from patients with ALS induces apoptosis selectively in motor neurones, and that the caspase-3 pathway is involved. This suggests that immunological mechanisms may contribute to the selective loss of motor neurones in ALS.

Cerebrospinal fluid from amyotrophic lateral sclerosis patients preferentially elevates intracellular calcium and toxicity in motor neurons via AMPA/kainate receptor

Several lines of evidence in the literature purport the contribution of glutamate mediated excitotoxicity in the etiology of amyotrophic lateral sclerosis (ALS) but the cellular mechanisms responsible for selective loss of motor neurons are still obscure. Elevation of intracellular Ca 2+ is considered as the early event in glutamate mediated cell injury. We have studied the changes in [Ca 2+] i and cytotoxicity in motor neurons and other spinal neurons in culture upon exposure to cerebrospinal fluid (CSF) from ALS patients. CSFs from 20 ALS patients and 20 disease control patients were examined. Eighteen out of twenty (90%) ALS–CSF samples induced a transient but pronounced elevation of [Ca 2+] i in neurons, whereas only 1/20 (5%) sample from disease control patients induced a marginal elevation of [Ca 2+] i. Strikingly the [Ca 2+] i rise was 2–3-fold higher and longer lasting in motor neurons in comparison to the other spinal neurons. Exposure of cells to ALS–CSF drastically decreased the survival rate of motor neurons to 32.26 ± 2.06% whereas a moderate decrease was observed in case of other spinal neurons (67.90 ± 2.04%). In cultures treated with disease control CSF, a small decrease was observed in the survival rate with 80.14 ± 2.00% and 90.07 ± 1.37% survival of motor neuron and other spinal neurons respectively. The AMPA/kainate receptor antagonist NBQX rendered significant protection against the ALS–CSF induced Ca 2+ influx and neurotoxicity while the NMDA receptor antagonist APV showed a mild effect. Our data demonstrate that the exposure of spinal cord neurons to ALS–CSF differentially elevates [Ca 2+] i and neurotoxicity in motor neurons by activation of glutamate receptors, the AMPA/kainate receptor playing the major role.

652. Adeno-Associated Vector Delivery of Gutamate Transporters in an ALS Mouse Model

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brainstem and spinal cord. The cause of motor neuron degeneration remains largely unknown and there is to date no effective therapy. Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS). Paradoxically, overactivation of glutamatergic neurons and extracellular accumulation of glutamate contributes to neuronal cell death observed in acute and chronic CNS insults, including ALS. The increased glutamate levels surrounding vulnerable motor neurons result from a pronounced loss of the excitatory amino acid transporter 2 (EAAT2) in affected ALS brain regions. EAAT2 (called GLT1 in rodents) is the predominant glutamate transporter in the CNS and is present on astrocytes. Loss of GLT-1 protein and function also occurs in mouse and rat ALS models.

Activation of the stress-activated MAP kinase, p38, but not JNK in cortical motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in transgenic mice

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, characterized by the degeneration of upper and lower motor neurons (MNs). Central nervous system features include a loss of Betz cells and other pyramidal cells from sensorimotor cortex. The intrinsic mechanism underlying this selective motor neuron loss has not been identified. A recent in vitro study has provided evidence of a novel programmed cell death (PCD) pathway that is unique to spinal cord MNs and is exacerbated by superoxide dismutase (SOD) mutations. This PCD pathway is triggered through the Fas receptor and involves the apoptosis signal-regulating kinase 1 (ASK1), the p38 MAP kinase, and the neuronal form of nitric oxide synthase (nNOS). Previously, we found significant increases in the numbers of ventral horn MNs immunopositive for these enzymes in the spinal cords of mutant SOD transgenic (G93A) mice as early as 60 days of age, suggesting that this pathway may be active in vivo. Since the upper MNs of ALS patients and G93A mice are also known to degenerate, the purpose of the present study was to investigate the possible activation of this PCD pathway in the MNs of the sensorimotor cortex of G93A transgenic mice. Compared to non-transgenic littermates, the G93A mice showed significant increases in the numbers of MNs immunopositive for the active (phosphorylated) forms of ASK1, p38, MKK3/6 (the known activator of p38), and also active caspase-3, as early as 60 days of age. Another stress-activated protein kinase, c-Jun N-terminal kinase (JNK), commonly activated in other neurodegenerative disorders such as Alzheimer's disease, showed no increases in G93A mice at any age. These results suggest that, not only has a PCD pathway been activated in the cortical MNs, but one that may be unique to ALS. Moreover, these findings suggest that earlier diagnosis and therapeutic intervention may be possible for successful treatment of ALS. Consequently, these enzymes may provide the biochemical markers to enable earlier diagnosis of ALS and molecular targets for the development of new therapeutic compounds.

The metabolic hypothesis in amyotrophic lateral sclerosis: insights from mutant Cu/Zn-superoxide dismutase mice

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by selective loss of motor neurons and progressive muscle atrophy. A subset of patients harbors point mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1), which allowed the generation of transgenic mice that express different SOD1 mutations and develop an ALS-like pathology. Recently, we reported in these mice the occurrence of a characteristic defect in energy homeostasis and the beneficial effect on the course of the disease of a high-energy fat-enriched diet. In this review, we discuss the implication of these findings in the light of classical clinical observations concerning metabolic alterations in human ALS.

Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective loss of motor neurons and progressive muscle wasting. Growing evidence indicates that mitochondrial dysfunction, not only occurring in motor neurons but also in skeletal muscle, may play a crucial role in the pathogenesis. In this regard, the life expectancy of the ALS G93A mouse line is extended by creatine, an intracellular energy shuttle that ameliorates muscle function. Moreover, a population of patients with sporadic ALS exhibits a generalized hypermetabolic state of as yet unknown origin. Altogether, these findings led us to explore whether alterations in energy homeostasis may contribute to the disease process. Here, we show important variations in a number of metabolic indicators in transgenic ALS mice, which in all shows a metabolic deficit. These alterations were accompanied early in the asymptomatic phase of the disease by reduced adipose tissue accumulation, increased energy expenditure, and concomitant skeletal muscle hypermetabolism. Compensating this energetic imbalance with a highly energetic diet extended mean survival by 20%. In conclusion, we suggest that hypermetabolism, mainly of muscular origin, may represent by itself an additional driven force involved in increasing motor neuron vulnerability.

Cell death in amyotrophic lateral sclerosis: interplay between neuronal and glial cells.

Mutations in the gene coding for the ubiquitous, anti-oxidant enzyme Cu,Zn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral sclerosis (fALS), a fatal disease characterized by selective loss of motor neurons. Expression of a mutant SOD1 typical of fALS patients restricted to either motor neurons or astrocytes is insufficient to generate a pathological phenotype in mouse models, suggesting that a deleterious interplay between different cell types is necessary for the pathogenesis of the disease. In this study, we demonstrate the actual role of a functional cross-talk between glial and neuronal cells expressing fALS mutant G93A-SOD1, where an increase in the production of reactive oxygen species occurs. We show that human glioblastoma cells expressing G93A-SOD1 induce activation of caspase-1, release of cytokines, and activation of apoptotic pathways in cocultured human neuroblastoma cells also expressing G93A-SOD1. Activation of caspase-1 and caspase-3 is observed also in neuroblastoma lines expressing other fALS-SOD1s (G37R, G85R, and I113T) cocultured with glioblastoma lines expressing the corresponding mutant enzymes. These effects are consequent to activation of inflammatory processes in G93A-glioblastoma cells stimulated by cocultured G93A-neuroblastoma. Furthermore, selective death of embryonal spinal motor neurons from G93A-SOD1 transgenic mice is induced by coculture with G93A-glioblastoma and prevented by inhibition of NO synthase. Proinflammatory cytokines, interferon-gamma, and nitric oxide are among the molecular signals exchanged between glial and neuronal cells that generate a functional interplay between the two cell types. This cross-talk may be crucial for the pathogenesis of SOD1-linked fALS but also for the more common sporadic form of the disease, where markers of increased oxidative stress and of glial activation have been found.

Monomeric Cu,Zn-superoxide Dismutase Is a Common Misfolding Intermediate in the Oxidation Models of Sporadic and Familial Amyotrophic Lateral Sclerosis

Proteinacious intracellular aggregates in motor neurons are a key feature of both sporadic and familial amyotrophic lateral sclerosis (ALS). These inclusion bodies are often immunoreactive for Cu,Zn-superoxide dismutase (SOD1) and are implicated in the pathology of ALS. On the basis of this and a similar clinical presentation of symptoms in the familial (fALS) and sporadic forms of ALS, we sought to investigate the possibility that there exists a common disease-related aggregation pathway for fALS-associated mutant SODs and wild type SOD1. We have previously shown that oxidation of fALS-associated mutant SODs produces aggregates that have the same morphological, structural, and tinctorial features as those found in SOD1 inclusion bodies in ALS. Here, we show that oxidative damage of wild type SOD at physiological concentrations ( approximately 40 microm) results in destabilization and aggregation in vitro. Oxidation of either mutant or wild type SOD1 causes the enzyme to dissociate to monomers prior to aggregation. Only small changes in secondary and tertiary structure are associated with monomer formation. These results indicate a common aggregation prone monomeric intermediate for wild type and fALS-associated mutant SODs and provides a link between sporadic and familial ALS.

The mRNA expression of AMPA type glutamate receptors in the primary motor cortex of patients with amyotrophic lateral sclerosis: an in situ hybridization study

The pathogenetic mechanisms leading to progressive neurodegeneration in amyotrophic lateral sclerosis (ALS) have not been fully elucidated. One possible factor responsible for the selective motor neuron loss in the motor cortex, brain stem and spinal cord is glutamate-induced excitotoxicity particularly mediated via α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) type glutamate receptors. Data about the expression pattern of AMPA receptors in the primary motor cortex are lacking so far. The pharmacological and physiological properties of AMPA receptors are defined by the heteromeric composition of the four different receptor subunits. Different expression patterns of these subunits at motor neurons may provide a molecular basis for increased vulnerability to excitotoxic damage. Using in situ hybridization histochemistry we did not detect any significant differences in the distribution of AMPA receptor mRNA in the motor cortex of ALS patients compared to controls.

Mutant superoxide dismutase 1 causes motor neuron degeneration independent of cyclin‐dependent kinase 5 activation by p35 or p25

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective loss of motor neurons in the brain and spinal cord. Neurotoxicity mediated by glutamate is thought to play a role in the neuronal death through intracellular calcium-dependent signaling cascades. Cyclin-dependent kinase 5 (Cdk5) has been proposed as one of the calcium-dependent mediators that may cause neuronal death observed in this disease. Cdk5 is activated in neurons by the association with its activators, p35 or p39. The calcium-activated protease calpain cleaves p35 to its truncated product, p25, which eventually causes the cellular mislocalization and prolonged activation of Cdk5. This deregulated Cdk5 induces cytoskeletal disruption and apoptosis. To examine whether inhibition of the calpain-mediated conversion of p35 to p25 can delay the disease progression of ALS, we generated double transgenic mice in which ALS-linked mutant copper/zinc superoxide dismutase 1 (SOD1G93A) was expressed in a p35-null background. The absence of p35 neither affected the onset and progression of motor neuron disease in the mutant SOD1 mice nor ameliorated the pathological lesions in these mice. Our results provide direct evidence that the pathogenesis of motor neuron disease in the mutant SOD1 mice is independent of the Cdk5 activation by p35 or p25.

Ultrastructural pattern of motor‐neurone degeneration in model of slow neurotoxicity in vitro

The chronic glutamate neurotoxicity is suggested to be involved in selective loss of motor neurones (MN) in amyotrophic lateral sclerosis (ALS). Evidence indicates that the loss of MN might be in part due to defective glutamate (GLU) transport resulting in elevation of synaptic glutamate. The in vitro model of slow neurodegeneration based on inhibition of GLU transport was used to evaluate the ultrastructural characteristics of neuronal and glial toxicity. The organotypic cultures of rat lumbar spinal cord maintaining the neurone–astrocyte metabolic interactions were subjected to GLU uptake blockers: threohydroxyaspartate (THA) and l‐transpyrrolidine‐2,4‐dicarboxylate (PDC). The MN exhibited vacuolar degeneration accompanied by presence of apoptotic profiles. The astroglial cells revealed some morphological abnormalities indicating their damage. The results suggest the involvement of both neuronal and glial components in the process of GLU‐mediated toxicity.

Molecular Mechanisms and Therapeutics of Amyotrophic Lateral SclerosisEdited by K.AbeAmsterdam, NetherlandsELSEVIER2000 ISBN: 0-444-50613-6

Book ReviewsMolecular Mechanisms and Therapeutics of Amyotrophic Lateral Sclerosis M. Zuheir Al-KawiMD, FACP, FAAN M. Zuheir Al-Kawi Senior Consultant Neurologist, Department of Neurosciences, King Faisal Specialist Hospital And Research Center, Riyadh, Saudi Arabi Search for more papers by this author Published Online:1 May 2003https://doi.org/10.5144/0256-4947.2003.227aSectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionThis book covers proceedings of an international symposium held in Japan on 22-24 September 2000 under the same title. The target readership include neurologists and neuroscientists interested in the disease and related degenerative disorders.Amyotrophic Lateral Sclerosis (ALS) received publicity, and consequently funding for research, after the death of a celebrity baseball player (Lou Gehrig) in the United States over 60 years ago. ALS remains a rapidly progressive and ultimately fatal neurological disorder, caused by the selective loss of motor neurons in the brain and spinal cord. In spite of advances in research and availability of an approved treatment; no meaningful influence on the long-term prognosis has been achieved. The exact mechanism of disease onset and progression is still elusive. Several susceptibility factors, genetic and others, may interact with environmental risk factors to precipitate the neuronal degenerative process. Treatment with riluzole had a statistically significant but clinically marginal benefit in delaying respirator dependency by a mean of 3 months. Scientifically, however, the treatment lent support to the approach of excitotoxic pathogenesis. Other leads on pathogenesis appeared a decade ago with the discovery of mutations in the gene of Cu/Zn superoxide dismutase (SOD1) in some patients affected with an uncommon form of ALS, namely the familial one, and later in developing transgenic mice expressing mutant with SOD1 gene.Most of the reported work comes from Japan, the host country for the congress. The presentations are grouped in chapters according to the research areas covered in the work presented. Leading “keynote” lectures to set the tone for state-of-the-art knowledge in the area, which could have added to the usefulness of the volume, are not consistently present in all chapters. Selective vulnerability of motor neurons is addressed as well as topics related to the dismutase mutations and glutamate toxicity among other putative mechanisms.As is inherent in congress series, coverage of different aspects of the subject is heterogeneous and dependent on submissions of researchers. Some pathological aspects and therapeutic approaches undergoing testing, like neurotrophic factors, are covered. Others like epidemiology received only one article.The book in general is a useful reference for neurologists and researchers dealing with ALS in particular and neurodegenerative diseases in general. Previous article Next article FiguresReferencesRelatedDetails Volume 23, Issue 3-4May-July 2003 Metrics History Published online1 May 2003 InformationCopyright © 2003, Annals of Saudi MedicinePDF download

The AMPA receptor antagonist NBQX prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis

α-Amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptor-mediated excitotoxicity has been implicated in the selective motor neuron loss in amyotrophic lateral sclerosis (ALS). The extent to which excitotoxicity contributes to motor neuron death remains incompletely understood. We therefore tested the potent and selective AMPA/kainate receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[ f]quinoxaline-7-sulfonamide (NBQX) on motor neurons in culture and in the G93A mouse model for familial ALS. Kainate-induced currents and changes in intracellular Ca 2+ concentration were measured with the perforated patch clamp technique combined with Ca 2+ imaging, motor neuron death was quantified by counting experiments and G93A mice were treated with saline or 8 mg/kg NBQX. NBQX blocked kainate-induced currents and concomitant changes in intracellular Ca 2+, prevented the kainate-induced motor neuron death, and prolonged survival of G93A mice.

Characterisation of catalytic nucleic acids targeting the survival of motor neuron messenger RNA

AbstractCatalytic nucleic acids have been used in a reverse genetics approach to study gene function. We are interested in applying this technology to study the autosomal recessive disease Spinal Muscular Atrophy (SMA) which is caused by loss of survival motor neuron gene (SMN) product leading to progressive motor neuron loss and muscular atrophy. Although the SMN gene is ubiquitously expressed, the cause for selective motor neuron loss is unknown. Embryonal lethality in mice has made it extremely difficult to generate animal models of SMA. We describe a procedure for selecting effective DNAzymes (DZ) and ribozymes (RZ) based on their ability to cleave the full length Smn mRNA at low magnesium concentrations, after a short time period, and at a low catalytic nucleic acid to target ratio. Using these criteria three effective RZ and DZ were generated. These results indicate that catalytic nucleic acids can effectively cleave Smn target RNA in an environment closely resembling that present in the cell and thus have potential for interference with Smn gene expression in cells and in vivo.

Topiramate protects against motor neuron degeneration in organotypic spinal cord cultures but not in G93A SOD1 transgenic mice

Topiramate is a novel anti-convulsant, structurally distinct from other known anti-convulsants. A number of independent studies suggest that topiramate has anti-excitotoxic properties. It has been found to diminish release of glutamate from neurons and block (-amino-3-hydoxy-5-methylisoxazole-4-proprionic acid glutamate receptor evoked currents. Since activation of non- N-methyl- d-aspartate glutamate receptors is thought to play a role in the selective loss of motor neurons in amyotrophic lateral sclerosis (ALS), we determined whether topiramate could protect against chronic glutamate-mediated motor neuron degeneration. An organotypic spinal cord culture system was used in which glutamate transport is inhibited by pharmacological blockade. After 3 weeks of treatment, topiramate was found to significantly prevent motor neuron degeneration in this culture model. However, the drug did not increase survival in G93A SOD1 transgenic mice, an animal model of ALS. These studies suggest that topiramate could be useful as a neuroprotectant, but were not effective in more complex motor injury paradigms such as the mouse model of ALS.

GluR2-dependent properties of AMPA receptors determine the selective vulnerability of motor neurons to excitotoxicity.

AMPA receptor-mediated excitotoxicity has been implicated in the selective motor neuron loss in amyotrophic lateral sclerosis. In some culture models, motor neurons have been shown to be selectively vulnerable to AMPA receptor agonists due to Ca(2+) influx through Ca(2+)-permeable AMPA receptors. Because the absence of GluR2 in AMPA receptors renders them highly permeable to Ca(2+) ions, it has been hypothesized that the selective vulnerability of motor neurons is due to their relative deficiency in GluR2. However, conflicting evidence exists about the in vitro and in vivo expression of GluR2 in motor neurons, both at the mRNA and at the protein level. In this study, we quantified electrophysiological properties of AMPA receptors, known to be dependent on the relative abundance of GluR2: sensitivity to external polyamines, rectification index, and relative Ca(2+) permeability. Cultured rat spinal cord motor neurons were compared with dorsal horn neurons (which are resistant to excitotoxicity) and with motor neurons that survived an excitotoxic insult. Motor neurons had a higher sensitivity to external polyamines, a lower rectification index, and a higher relative Ca(2+) permeability ratio than dorsal horn neurons. These findings confirm that motor neurons are relatively deficient in GluR2. The AMPA receptor properties correlated well with each other and with the selective vulnerability of motor neurons because motor neurons surviving an excitotoxic event had similar characteristics as dorsal horn neurons. These data indicate that the relative abundance of GluR2 in functional AMPA receptors may be a major determinant of the selective vulnerability of motor neurons to excitotoxicity in vitro.

Genetically engineered mouse models of neurodegenerative diseases.

Recent research has significantly advanced our understanding of the molecular mechanisms of neurodegenerative diseases, including Alzheimer's disease (AD) and motor neuron disease. Here we emphasize the use of genetically engineered mouse models that are instrumental for understanding why AD is a neuronal disease, and for validating attractive therapeutic targets. In motor neuron diseases, Cu/Zn superoxide dismutase and survival motor neuron mouse models are useful in testing disease mechanisms and therapeutic strategies for amyotrophic lateral sclerosis (ALS) and spinal motor atrophy, respectively, but the mechanisms that account for selective motor neuron loss remain uncertain. We anticipate that, in the future, therapies based on understanding disease mechanisms will be identified and tested in mouse model systems.