Population Pharmacokinetics of Unbound and Total Teicoplanin in Critically Ill Pediatric Patients.

BACKGROUND AND OBJECTIVES: Teicoplanin is a highly protein-bound antibiotic, increasingly used to treat serious Gram-positive infections in critically ill children. Maturational and pathophysiological intensive care unit-related changes often lead to altered pharmacokinetics. In this study, the objectives were to develop a pediatric population-pharmacokinetic model of unbound and total teicoplanin concentrations, to investigate the impact of plasma albumin levels and renal function on teicoplanin pharmacokinetics, and to evaluate the efficacy of the current weight-based dosing regimen. METHODS: An observational pharmacokinetic study was performed and blood samples were collected for quantification of unbound and total concentrations of teicoplanin after the first dose and in assumed steady-state conditions. A population-pharmacokinetic analysis was conducted using a standard sequential approach and Monte Carlo simulations were performed for a probability of target attainment analysis using previously published pharmacokinetic-pharmacodynamic targets. RESULTS: A two-compartment model with allometric scaling of pharmacokinetic parameters and non-linear plasma protein binding best described the data. Neither the inclusion of albumin nor the renal function significantly improved the model and no other covariates were supported for inclusion in the final model. The probability of target attainment analysis showed that the standard dosing regimen does not satisfactory attain the majority of the proposed targets. CONCLUSIONS: We successfully characterized the pharmacokinetics of unbound and total teicoplanin in critically ill pediatric patients. The highly variable unbound fraction of teicoplanin could not be predicted using albumin levels, which may support the use of therapeutic drug monitoring of unbound concentrations. Poor target attainment was shown for the most commonly used dosing regimen, regardless of the pharmacokinetic-pharmacodynamic target evaluated.

External factors affecting fertility, and how to correct their impact.

Fertility of both men and women has been negatively influenced by external factors and life style in recent decennia. Mechanisms of hormone disruption, oxidative damage, and epigenetic DNA changes play a pivotal role in this process. In Belgium, strict regulations have been imposed to reduce the exposure to xeno-estrogens, which has resulted in a partial recovery of sperm quality. At the other hand, more couples require in vitro fertilisation (IVF) whereby ovarian stimulation may be associated with epigenetic DNA hyper-methylation of follicular cells, and increased risk of carcinogenesis among offspring. In order to reduce the health risks for the offspring it is recommended to optimize the oxidative, epigenetic and metabolic situation of both parents by means of lifestyle adaptation, and the use of appropriate food supplementation before conception and during pregnancy.

Management of dystonia in Europe: a survey of the European network for the study of the dystonia syndromes.

BACKGROUND AND PURPOSE: Dystonia is difficult to recognize due to its large phenomenological complexity. Thus, the use of experts in dystonia is essential for better recognition and management of dystonia syndromes (DS). Our aim was to document managing strategies, facilities and expertise available in various European countries in order to identify which measures should be implemented to improve the management of DS. METHODS: A survey was conducted, funded by the Cooperation in Science and Technology, via the management committee of the European network for the study of DS, which is formed from representatives of the 24 countries involved. RESULTS: Lack of specific training in dystonia by general neurologists, general practitioners as well as other allied health professionals was universal in all countries surveyed. Genetic testing for rare dystonia mutations is not readily available in a significant number of countries and neurophysiological studies are difficult to perform due to a lack of experts in this field of movement disorders. Tetrabenazine is only readily available for treatment of dystonia in half of the surveyed countries. Deep brain stimulation is available in three-quarters of the countries, but other surgical procedures are only available in one-quarter of countries. CONCLUSIONS: Internationally, collaboration in training, advanced diagnosis, treatment and research of DS and, locally, in each country the creation of multidisciplinary teams for the management of dystonia patients could provide the basis for improving all aspects of dystonia management across Europe.

Dual-task-related neural connectivity changes in patients with Parkinson' disease.

BACKGROUND AND OBJECTIVES: Dual-task (DT) gait impairment in people with Parkinson's disease (PD) and specifically in those with freezing of gait (FOG), reflects attentional dependency of movement. This study aimed to elucidate resting-state brain connectivity alterations related to DT gait abnormalities in PD with and without FOG. METHODS: PD patients (n=73) and healthy age-matched controls (n=20) underwent DT gait analysis and resting-state functional Magnetic Resonance Imaging (rs-MRI) while 'off' medication. Patients were classified as freezer (n=13) or non-freezer (n=60). Functional connectivity (FC) alterations between PD and controls and between patient subgroups were assessed in regions of interest (ROIs) within the fronto-parietal and motor network. RESULTS: PD had longer stance times, shorter swing times and more step length asymmetry during DT gait and needed more time and steps during DT turning compared to controls. Additionally, freezers showed similar impairments and longer double support times compared to non-freezers during DT gait. PD demonstrated hyper-connectivity between the inferior parietal lobule and premotor cortex (PMC) and between the cerebellum and the PMC and M1. FOG-specific hypo-connectivity within the striatum and between the caudate and superior temporal lobe and hyper-connectivity between the dorsal putamen and precuneus was correlated with worse DT performance. CONCLUSION: PD showed FC alterations in DT-related networks, which were not correlated to DT performance. However, FOG-specific FC alterations in DT-related regions involving the precuneus and striatum were correlated to worse DT performance, suggesting that the balance between cognitive and motor networks is altered.

Center of mass trajectories during turning in patients with Parkinson's disease with and without freezing of gait.

BACKGROUND: Despite the strong relationship between freezing of gait (FOG) and turning in Parkinson's disease (PD), few studies have addressed specific postural characteristics during turning that might contribute to freezing. METHODS: Thirty participants with PD (16 freezers, 14 non-freezers) (all tested OFF medication) and 14 healthy controls walked 5 meters and turned 180° in a 3D gait laboratory. COM behavior was analyzed during four turning quadrants of 40° between 10° and 170° pelvic rotation and during 40° before actual FOG episodes. These pre-FOG segments were compared with similar turning sections in turns of freezers without FOG. Outcome parameters were turn time, COM distance, COM velocity, step width and the medial- and anterior COM position. RESULTS: Turn time was increased in freezers compared to non-freezers (p=.000). No differences were found regarding COM distance and velocity during turning quadrants between groups and between freezers' pre-FOG segments and similar turning segments without FOG. Medial COM deviation was reduced in PD patients compared to controls (p=.004), but no differences were found between freezers and non-freezers. In turns with freezing, turn time increased (p=.005) and step width decreased (p=.025) pre-FOG. Freezers also showed a less medial (p=.020) and more anterior (p=.016) COM position pre-FOG compared to turning sections without FOG. CONCLUSIONS: Our results revealed no subgroup differences in COM behavior during uninterrupted turning. However, we found a reduced medial deviation, a forward COM shift and a decreased step width in freezers just before FOG episodes. These abnormalities may play a causal role, as they could hamper stability and fluent weight shifting necessary for continued stepping during turning.

Effects of deep brain stimulation of the subthalamic nucleus on freezing of gait in Parkinson's disease: a prospective controlled study.

BACKGROUND: Freezing of gait (FOG) is a debilitating gait disorder in Parkinson's disease (PD) with partial responsiveness to dopaminergic medication. To date, notions about the effects of subthalamic deep brain stimulation (STN-DBS) on FOG remain controversial. OBJECTIVES: To compare the effects of bilateral STN-DBS and continued best medical treatment (BMT) on FOG occurrence, FOG severity and clinical outcomes in PD patients at 6 and 12 months follow-up. METHODS: In this prospective, controlled study, 41 PD patients with at least 5 years disease duration participated. Twenty-four subjects (20 with FOG) were treated with STN-DBS and seventeen (15 with FOG) continued BMT. The primary outcome was the New Freezing of Gait Questionnaire (NFOGQ) at 6 months postsurgery. Other outcomes were the NFOGQ at 12 months and clinical outcomes (Unified Parkinson's Disease Rating Scale III (UPDRS III), timed gait, falls and quality of life) at both time points. RESULTS: STN-DBS increased the likelihood to convert from being a freezer to a non-freezer at 6 and 12 months follow-up (relative risk reduction=0.4). However, 45% of baseline freezers still experienced FOG 6 and 12 months postsurgery although with reduced severity. Three baseline non-freezers (1/2 BMT-treated, 2/4 STN-DBS-treated) developed FOG during follow-up. STN-DBS-induced benefits on FOG were mostly mediated by baseline levodopa equivalent dose, altered medication-intake and reduced motor fluctuations. CONCLUSIONS: In contrast to continued BMT, STN-DBS reduced FOG occurrence and severity at 6 months postsurgery with largely sustained effects at 12 months follow-up. Longer follow-up periods are needed to test whether FOG improvements after STN-DBS persist with disease progression.

The neural correlates of upper limb motor blocks in Parkinson's disease and their relation to freezing of gait.

Due to basal ganglia dysfunction, bimanual motor performance in Parkinson patients reportedly relies on compensatory brain activation in premotor-parietal-cerebellar circuitries. A subgroup of Parkinson's disease (PD) patients with freezing of gait (FOG) may exhibit greater bimanual impairments up to the point that motor blocks occur. This study investigated the neural mechanisms of upper limb motor blocks and explored their relation with FOG. Brain activation was measured using functional magnetic resonance imaging during bilateral finger movements in 16 PD with FOG, 16 without FOG (PD + FOG and PD - FOG), and 16 controls. During successful movement, PD + FOG showed decreased activation in right dorsolateral prefrontal cortex (PFC), left dorsal premotor cortex (PMd), as well as left M1 and bilaterally increased activation in dorsal putamen, pallidum, as well as subthalamic nucleus compared with PD - FOG and controls. On the contrary, upper limb motor blocks were associated with increased activation in right M1, PMd, supplementary motor area, and left PFC compared with successful movement, whereas bilateral pallidum and putamen activity was decreased. Complex striatofrontal activation changes may be involved in the difficulties of PD + FOG to perform bimanual movements, or sequential movements in general. These novel results suggest that, whatever the exact underlying cause, PD + FOG seem to have reached a saturation point of normal neural compensation and respond belatedly to actual movement breakdown.

Turning and unilateral cueing in Parkinson's disease patients with and without freezing of gait.

BACKGROUND: Freezing of gait (FOG) is one of the most disabling symptoms in Parkinson's disease (PD), and cueing has been reported to improve FOG during straight-line walking. Studies on how cueing affects FOG during turning are lacking. Given the asymmetrical nature of turning and the asymmetrical disease expression, we aimed to gain a new perspective on how unilateral cueing may alleviate FOG. OBJECTIVE: To explore disease dominance and turning side as contributing factors to turning problems and FOG and to investigate the effect of unilateral cueing. METHODS: In the first study, 13 PD patients with FOG (freezers) and 13 without FOG (nonfreezers) turned toward their disease-dominant and nondominant side (off medication). During the second study, 16 freezers and 14 nonfreezers turned with and without a unilateral auditory cue at -10% of preferred cadence. Total number of steps, turn duration, cadence, and FOG episodes were measured using VICON. RESULTS: Cadence, but not FOG frequency, was higher when turning toward the disease-dominant side. FOG started more frequently (64.9%) on the inner side of the turning cycle. Unilateral cueing seemed to prevent FOG in most patients, irrespective of the side at which the cue was offered. A carryover effect was found for cadence during turning, but the effect on FOG disappeared when the cue was removed. CONCLUSIONS: The occurrence of FOG is not influenced by turning toward the disease-dominant or nondominant side, which is confirmed by the fact that it does not make a difference at which side unilateral cueing is applied. Cueing reduces FOG during turning, but these effects disappear dramatically after cue removal. This raises further questions as to the influence of training on cue dependency and on the feasibility of either continuous application of cues or using cognitive strategies as an alternative.

Anesthesia and perioperative management for a patient with Ullrich syndrome undergoing surgery for scoliosis.

Ullrich syndrome is a rare congenital hypotonic-sclerotic muscular disorder in which affected children develop a slowly progressive scoliosis and contractures and limpness of joints. The disease causes increasingly invalidating contractures and hardening of the muscles of the neck and trunk. While this neuromuscular type of scoliosis is progressive, patients rarely attain the point of surgery due to their compromised general medical condition. This may explain the current lack of outcome data and the paucity of information on perioperative management for patients with Ullrich syndrome undergoing major surgery. The purpose of this report was therefore to describe our first experience with the perioperative and anesthetic management of a 15-year-old boy presenting with Ullrich syndrome and a secondary invalidating scoliosis. The specific challenges of this condition characterized by severe restrictive lung disease and a challenging airway abnormality are discussed.

Myoclonus-dystonia: clinical and genetic evaluation of a large cohort.

BACKGROUND: Myoclonus-dystonia (M-D) is an autosomal dominant inherited movement disorder. Various mutations within the epsilon-sarcoglycan (SGCE) gene have been associated with M-D, but mutations are detected in only about 30% of patients. The lack of stringent clinical inclusion criteria and limitations of mutation screens by direct sequencing might explain this observation. METHODS: Eighty-six M-D index patients from the Dutch national referral centre for M-D underwent neurological examination and were classified according to previously published criteria into definite, probable and possible M-D. Sequence analysis of the SGCE gene and screening for copy number variations were performed. In addition, screening was carried out for the 3 bp deletion in exon 5 of the DYT1 gene. RESULTS: Based on clinical examination, 24 definite, 23 probable and 39 possible M-D patients were detected. Thirteen of the 86 M-D index patients carried a SGCE mutation: seven nonsense mutations, two splice site mutations, three missense mutations (two within one patient) and one multiexonic deletion. In the definite M-D group, 50% carried an SGCE mutation and one single patient in the probable group (4%). One possible M-D patient showed a 4 bp deletion in the DYT1 gene (c.934_937delAGAG). CONCLUSIONS: Mutation carriers were mainly identified in the definite M-D group. However, in half of definite M-D cases, no mutation could be identified. Copy-number variations did not play a major role in the large cohort.

Predictors of fitness to drive in people with Parkinson disease.

OBJECTIVE: To develop an efficient clinical screening battery to accurately predict the fitness to drive in people with Parkinson disease (PD). METHODS: This prospective study included 80 participants: 40 patients with PD and 40 healthy age- and sex-matched control subjects. All participants were assessed using a driving simulator, a driving history survey, and the Clinical Dementia Rating. The patients with PD also underwent a clinical test battery and an evaluation of fitness to drive performed by an official center, which included visual, cognitive, and on-road tests. A two-class decision from this driving assessment center was the main outcome measure. RESULTS: A screening battery assessing four clinical variables (disease duration, contrast sensitivity, Clinical Dementia Rating, and motor part of the Unified Parkinson's Disease Rating Scale) provided the best model (R(2) = 0.52) to predict the fitness to drive and correctly classified 36 (90%) of the patients with PD as pass or fail (sensitivity = 91%, specificity = 90%). The Test Ride for Investigating Practical fitness to drive (TRIP) driving simulator score discriminated significantly between drivers with PD and their healthy peers (p = 0.0008). When the TRIP driving simulator score was added to the clinical model, the total explained variance increased (R(2) = 0.60) and correctly classified 39 (97.5%) of drivers with PD into the pass/fail category (sensitivity = 91%, specificity = 100%). CONCLUSIONS: A short clinical screening battery that measures disease duration, contrast sensitivity, cognitive and motor functions can predict fitness to drive in people with Parkinson disease with a high degree of accuracy.

Subcellular localization of calcium-permeable AMPA receptors in spinal motoneurons.

Activation of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has been linked to potent effects on survival and dendritic outgrowth of spinal motoneurons. Ca(2+) permeability of AMPA receptors is controlled by the GluR2 subunit. Whole-cell electrophysiological studies have suggested that GluR2-containing and GluR2-lacking AMPA receptors may coexist in individual motoneurons. However, there has not been a direct demonstration of heterogeneity in AMPA receptor subunit composition in single motoneurons, nor of distinct subcellular distributions of GluR2-containing and GluR2-lacking receptors. In the present study, we have used confocal microscopy, immunocytochemistry and Ca(2+) imaging to characterize the subcellular localization of AMPA receptors in cultured rat spinal motoneurons. Immunoreactivity for GluR2 and GluR4 was concentrated in clusters, the vast majority of which were found in dendrites at synapses. Double-labelling for GluR2 and GluR4 revealed variability in relative expression of GluR2 and GluR4 between clusters within individual motoneurons; most AMPA receptor clusters were immunoreactive for both GluR2 and GluR4, but a significant minority of clusters were immunoreactive for GluR2 only or for GluR4 only. The majority of GluR2-immunonegative AMPA receptor clusters was present in dendrites, but the relative proportion of GluR2-immunonegative and GluR2-immunopositive clusters was similar in dendrites and soma. Imaging of [Ca(2+)](i) rises triggered by AMPA receptor activation confirmed Ca(2+) influx in motoneuron dendrites. These findings strongly support a model in which GluR2-containing and GluR2-lacking AMPA receptors coexist in motoneurons, clustered at synapses, and mixed in a relative proportion that varies considerably between cell membrane microdomains.

Ca(2+)-permeable AMPA receptors and selective vulnerability of motor neurons.

To evaluate the role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis (ALS), we compared the sensitivity of motor neurons and that of dorsal horn neurons to kainic acid (KA). Short exposure to KA resulted in the death of motor neurons, while dorsal horn neurons were unaffected. This selective motor neuron death was completely dependent on extracellular Ca(2+) and insensitive to inhibitors of voltage-operated Ca(2+) or Na(+) channels. It was also completely inhibited by the specific AMPA antagonist LY300164 and by Joro spider toxin (JSTx), a selective blocker of AMPA receptors that lack the edited GluR2 subunit. KA selectively killed those motor neurons that stained positive for the Co(2+) histochemical staining, a measure for the presence of Ca(2+)-permeable AMPA receptors. These results suggest that Ca(2+) entry via Ca(2+)-permeable AMPA receptors is responsible for the selective motor neuron death. As the Ca(2+) permeability of the AMPA receptor is regulated by its GluR2 subunit, we stained motor neurons for GluR2. Immunoreactivity was present in all motor neurons, albeit to a variable degree. However, double-staining experiments demonstrated that motor neurons clearly expressing GluR2, also expressed Ca(2+)-permeable AMPA receptors. This indicates that despite the abundant expression of GluR2, this subunit is excluded from a subset of AMPA receptors and that the activation of these receptors is responsible for the selective motor neuron death.

AMPA receptor current density, not desensitization, predicts selective motoneuron vulnerability.

Spinal motoneurons are more susceptible to AMPA receptor-mediated injury than are other spinal neurons, a property that has been implicated in their selective degeneration in amyotrophic lateral sclerosis (ALS). The aim of this study was to determine whether this difference in vulnerability between motoneurons and other spinal neurons can be attributed to a difference in AMPA receptor desensitization and/or to a difference in density of functional AMPA receptors. Spinal motoneurons and dorsal horn neurons were isolated from embryonic rats and cultured on spinal astrocytes. Single-cell RT-PCR quantification of the relative abundance of the flip and flop isoforms of the AMPA receptor subunits, which are known to affect receptor desensitization, did not reveal any difference between the two cell populations. Examination of AMPA receptor desensitization by patch-clamp electrophysiological measurements on nucleated and outside-out patches and in the whole-cell mode also yielded similar results for the two cell groups. However, AMPA receptor current density was two- to threefold higher in motoneurons than in dorsal horn neurons, suggesting a higher density of functional AMPA receptors in motoneuron membranes. Pharmacological reduction of AMPA receptor current density in motoneurons to the level found in dorsal horn neurons eliminated selective motoneuron vulnerability to AMPA receptor activation. These results suggest that the greater AMPA receptor current density of spinal motoneurons may be sufficient to account for their selective vulnerability to AMPA receptor agonists in vitro.

AMPA receptor calcium permeability, GluR2 expression, and selective motoneuron vulnerability.

AMPA receptor-mediated excitotoxicity is proposed to play a major pathogenic role in the selective motoneuron death of amyotrophic lateral sclerosis. Motoneurons have been shown in various models to be more susceptible to AMPA receptor-mediated injury than other spinal neurons. It has been hypothesized that this selective vulnerability of motoneurons is caused by the expression of highly Ca(2+)-permeable AMPA receptors and a complete or relative lack of the AMPA receptor subunit Glu receptor 2 (GluR2). The aim of this study was to quantify the relative Ca(2+) permeability of AMPA receptors and the fractional expression of GluR2 in motoneurons by combining whole-cell patch-clamp electrophysiology and single-cell RT-PCR and to compare these properties with those of dorsal horn neurons. Spinal motoneurons and dorsal horn neurons were isolated from embryonic rats and cultured on spinal astrocytes. As in previous studies, motoneurons were significantly more vulnerable to AMPA and kainate than dorsal horn neurons. However, all motoneurons expressed GluR2 mRNA ( approximately 40% of total AMPA receptor subunit mRNA), and their AMPA receptors had intermediate whole-cell relative Ca(2+) permeability (P(Ca(2+))/P(Cs(+)) approximately 0. 4). AMPA receptor P(Ca(2+))/P(Cs(+)) and the relative abundance of GluR2 varied more widely in dorsal horn neurons than in motoneurons, but the mean values did not differ significantly between the two cell populations. GluR2 was virtually completely edited at the Q/R site both in motoneurons and dorsal horn neurons. These results indicate that the selective vulnerability of motoneurons to AMPA receptor agonists is not determined solely by whole-cell relative Ca(2+) permeability of AMPA receptors.

Ca(2+) permeation of AMPA receptors in cerebellar neurons expressing glu receptor 2.

AMPA receptors in cultured cerebellar neurons were characterized by whole-cell electrophysiological studies and single cell PCR-based quantitation of subunit mRNA expression. Purkinje neurons consistently expressed high levels of Glu receptor 2 (GluR2) mRNA and AMPA receptors with low but nonzero Ca(2+) permeability. Other cerebellar neurons expressed AMPA receptors with a wide range of Ca(2+) permeability and of fractional GluR2. These properties correlated on a cell-by-cell basis. Their relationship was well fit by a model that assumed stochastic assembly of subunits and GluR2 dominance in controlling divalent cation permeation, suggesting that AMPA receptor properties in individual neurons may be determined primarily by relative levels of subunit transcription. A fraction of receptors, lacking GluR2, can contribute a highly Ca(2+)-permeable component to AMPA receptor responses, even in cells expressing GluR2.

Tissue-type plasminogen activator is not required for kainate-induced motoneuron death in vitro.

Spinal motoneurons are highly vulnerable to kainate both in vivo and in vitro. Tissue-type plasminogen activator (tPA) and plasmin have recently been shown to mediate kainate-induced neuronal death in the mouse hippocampus in vivo. The aim of the present study was to determine whether tPA also mediates the kainate-induced death of motoneurons in vitro. A motoneuron-enriched neuronal population was isolated from the ventral spinal cord of wild-type (WT) and tPA-deficient (tPA-/-) mouse embryos. WT and tPA-/- neurons were cultured on WT and tPA-/- spinal glial feeder layers, respectively. WT and tPA-/- co-cultures were morphologically indistinguishable. Expression of tPA in WT co-cultures was demonstrated using RT-PCR. WT and tPA-/- co-cultures were exposed to kainate for 24 h. The neurotoxic effect of kainate did not differ significantly between WT and tPA-/- cultures. The plasmin inhibitor alpha2-antiplasmin did not protect WT neurons against kainate-induced injury. These results indicate that the plasmin system is not a universal mediator of kainate-induced excitotoxicity.

Glial cells potentiate kainate-induced neuronal death in a motoneuron-enriched spinal coculture system.

AMPA/kainate receptor-mediated excitotoxicity is believed to play a pathogenic role in amyotrophic lateral sclerosis. To further characterize the mechanisms involved in AMPA/kainate receptor-mediated motoneuron injury, we investigated the influence of spinal glial cells on kainate-induced motoneuron death in vitro. A motoneuron-enriched neuronal population was obtained from embryonic mouse spinal cord by metrizamide density centrifugation. This population was cultured either on a pre-established glial feeder layer of ventral spinal origin (coculture) or in glia-free conditions (monoculture). Glial feeder layers significantly enhanced basal survival of neurons, and supported neuronal differentiation as judged by neuronal morphology and expression of the motoneuron markers peripherin and SMI-32. Neuronal vulnerability to kainate was two- to three-fold higher in coculture than in monoculture, and increased significantly with time in coculture. The effects of glial feeder layers on neuronal basal survival, differentiation and kainate vulnerability were not mimicked by conditioned medium from glial cells. The increase in neuronal kainate vulnerability with time in coculture was associated with a marked rise in the proportion of cocultured neurons possessing Ca2+-permeable AMPA/kainate receptors, as determined by kainate-activated Co2+-uptake. Neurons in monoculture were unstained by kainate-activated Co2+-uptake. Neurons were immunoreactive to specific antibodies against the AMPA receptor subunits GluR1 and GluR2 both in monoculture and coculture. This study indicates that motoneuron differentiation in coculture is associated with increased vulnerability to kainate and increased expression of Ca2+-permeable AMPA/kainate receptors. In this paradigm glial cells support basal survival and differentiation of neurons, but potentiate kainate-induced neuronal death.