Cholinergic parameters and the retrieval of learned and re-learned spatial information: a study using a model of Wernicke-Korsakoff Syndrome

This is a factorial (2 x 2 x 2) spatial memory and cholinergic parameters study in which the factors are chronic ethanol, thiamine deficiency and naivety in Morris water maze task. Both learning and retention of the spatial version of the water maze were assessed. To assess retrograde retention of spatial information, half of the rats were pre-trained on the maze before the treatment manipulations of pyrithiamine (PT)-induced thiamine deficiency and post-tested after treatment (pre-trained group). The other half of the animals was only trained after treatment to assess anterograde amnesia (post-trained group). Thiamine deficiency, associated to chronic ethanol treatment, had a significant deleterious effect on spatial memory performance of post-trained animals. The biochemical data revealed that chronic ethanol treatment reduced acetylcholinesterase (AChE) activity in the hippocampus while leaving the neocortex unchanged, whereas thiamine deficiency reduced both cortical and hippocampal AChE activity. Regarding basal and stimulated cortical acetylcholine (ACh) release, both chronic ethanol and thiamine deficiency treatments had significant main effects. Significant correlations were found between both cortical and hippocampal AChE activity and behaviour parameters for pre-trained but not for post-trained animals. Also for ACh release, the correlation found was significant only for pre-trained animals. These biochemical parameters were decreased by thiamine deficiency and chronic ethanol treatment, both in pre-trained and post-trained animals. But the correlation with the behavioural parameters was observed only for pre-trained animals, that is, those that were retrained and assessed for retrograde retention.     

Morphological abnormalities in nitric-oxide-synthase-positive striatal interneurons of schizophrenic patients

Schizophrenia has been suggested to be a neurodevelopmental disorder, and nitric-oxide-synthase (NOS)-positive neurons were shown to be involved in distorted cortical development in schizophrenia. Here we investigated whether nitrinergic neurons in the striatum of schizophrenic patients also display abnormalities regarding distribution or morphology. To do so, postmortem putaminal sections of schizophrenic subjects were examined by means of nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) staining and NOS immunohistochemistry. NOS-positive neurons were counted and analyzed morphologically. Abnormalities regarding morphology or number of NOS-containing neurons could be found in the putamen of schizophrenics (n = 3), but not controls (n = 5). Neurons were either of abnormal size and branching pattern, or they were markedly reduced (130 +/- 44 vs. 54 +/- 62 NADPHd-positive somata/mm(3) putamen; p < 0.0001). Striatal nitrinergic interneurons might thus be involved in the pathogenesis of at least some forms of schizophrenia. Studies on larger samples are however needed to further corroborate this finding.     

Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice

Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is thought to result from deficient intracellular cholesterol and/or ganglioside trafficking. We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1(-/-) mice). We confirmed previous results showing that a single injection of 250 microg of allopregnanolone on postnatal day 7 significantly extended the life span of Npc1(-/-) mice. This caused a marked difference in the weight curves of the treated mice but no statistical difference in the Rota-Rod performance. T2-weighted MRI and diffusion tensor imaging (DTI) of treated mice showed values of signal intensity and fractional anisotropy closer to those of wild-type mice than those of untreated Npc1(-/-) mice. Neuropathology showed that day-7 treatment markedly suppressed astrocyte reaction and significantly reduced microglial activation. Furthermore, the steroid treatment also increased myelination in brains of Npc1(-/-) mice. Similar effects of allopregnanolone treatment were observed in Npc1(-/-), mdr1a(-/-) double-mutant mice, which have a deficient blood-brain barrier, resulting in increased steroid uptake. The effects on survival and weight loss of a single injection on day 7 followed by injections every 2 weeks were also evaluated in Npc1(-/-) mice, and the beneficial effects were found to be greater than with the single injection at day 7. We conclude that allopregnanolone treatment significantly ameliorates several symptoms of NPC in Npc1(-/-) mice, presumably by effects on myelination or neuronal connectivity.     

Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy

Antiepileptic drugs, particularly cytochrome P450 enzyme inducers, are associated with disorders of bone metabolism. We studied premenopausal women with epilepsy receiving antiepileptic drug monotherapy (phenytoin, carbamazepine, valproate, and lamotrigine). Subjects completed exercise and nutrition questionnaires and bone mineral density studies. Serum was analyzed for indices of bone metabolism including calcium, 25-hydroxyvitamin D, parathyroid hormone, insulin growth factor I, insulin binding protein III, and bone formation markers, bone-specific alkaline phosphatase, and osteocalcin. Urine was analyzed for cross-linked N-telopeptide of type I collagen, a bone resorption marker. Calcium concentrations were significantly less in subjects receiving carbamazepine, phenytoin, and valproate than in those receiving lamotrigine (p = 0.008). Insulin growth factor-I was significantly reduced in subjects receiving phenytoin compared with those receiving lamotrigine (p = 0.017). Subjects receiving phenytoin had significantly greater levels of bone-specific alkaline phosphatase (p = 0.007). Our results demonstrate that phenytoin is associated with changes in bone metabolism and increased bone turnover. The lower calcium concentrations in subjects taking carbamazepine or valproate compared with those taking other antiepileptic drugs suggest that these antiepileptic drugs may have long-term effects. Subjects receiving lamotrigine had no significant reductions in calcium or increases in markers of bone turnover, suggesting this agent is less likely to have long-term adverse effects on bone.     

A rare truncating mutation in ADH1C (G78Stop) shows significant association with Parkinson disease in a large international sample

BACKGROUND: Alcohol dehydrogenases (ADHs) may be involved in the pathogenesis of neurodegenerative disorders because of their multiple roles in detoxification pathways and retinoic acid synthesis. In a previous study, significant association of an ADH class IV allele with Parkinson disease (PD) was found in a Swedish sample. PATIENTS: The previously associated single-nucleotide polymorphism plus 12 further polymorphisms in the ADH cluster on human chromosome 4q23 were screened for association in an extension of the original sample that now included 123 Swedish PD patients and 127 geographically matched control subjects. A rare nonsense single-nucleotide polymorphism in ADH1C (G78stop, rs283413) was identified in 3 of these patients but in no controls. To obtain sufficient power to detect a possible association of this rare variant with disease, we screened a large international sample of 1076 PD patients of European ancestry and 940 matched controls. RESULTS: The previously identified association with an ADH class IV allele remained significant (P<.02) in the extended Swedish study. Furthermore, in the international collaboration, the G78stop mutation in ADH1C was found in 22 (2.0%) of the PD patients but only in 6 controls (0.6%). This association was statistically significant (chi(2)(1) = 7.5; 2-sided P = .007; odds ratio, 3.25 [95% confidence interval, 1.31-8.05]). In addition, the G78stop mutation was identified in 4 (10.0%) of 40 Caucasian index cases with PD with mainly hereditary forms of the disorder. CONCLUSION: Findings presented herein provide further evidence for mutations in genes encoding ADHs as genetic risk factors for PD.     

Epilepsy and neurocysticercosis in Atahualpa: a door-to-door survey in rural coastal Ecuador

PURPOSE: To determine the prevalence of epilepsy and the role of neurocysticercosis in the occurrence of epilepsy in Atahualpa. METHODS: We used a door-to-door survey to detect subjects with epileptic seizures, to collect a blood sample for determination of anticysticercal antibodies, and to evaluate social characteristics of the population, including household pig ownership. Neurologists examined suspected cases and a sample of negative individuals. Then patients with epilepsy, as well as age- and sex-matched controls, underwent a head computed tomography (CT) and a scalp EEG. RESULTS: The questionnaire was answered by 2,415 of 2,548 residents of Atahualpa, and cysticercosis serology was performed in 1,687 consenting individuals. Cysticercosis seroprevalence was 145 (8.6%) per 1,686). Neurologic examination confirmed 24 patients with epilepsy (crude prevalence, 9.9 per 1,000 population, and 10.8 per 1,000 when adjusted to the United States population). After adjustment by age, sex, and pig raising, positive serology was strongly associated with epilepsy (odds ratio (OR), 4.16; 95% confidence interval (CI), 1.6-11.2). CT findings compatible with neurocysticercosis were found in five patients with epilepsy and also were more frequent than in controls, although this did not reach statistical significance (five of 19 vs. one of 19; p = 0.125, McNemar's test). Besides these five cases, three other patients with epilepsy had positive serology (one with a normal CT and two who did not have a CT). CONCLUSIONS: Neurocysticercosis is associated with one-third of cases of epilepsy in Atahualpa and may be a major contributory factor for the excess fraction of epilepsy seen in this population.     

Glial transcytosis of a photoreceptor-secreted signaling protein, retinoschisin

In vitro studies have clearly shown that signaling/guidance proteins can diffuse to their targets. However, it is unclear whether they can travel by diffusion in vivo, or if they are distributed in the tissue by an active mechanism. Retinoschisin, a signaling molecule related to neuropilins, is synthesized and secreted by photoreceptor cells in the outer retina; then it interacts with inner retinal cells contributing to synaptic organization and optic nerve fiber integrity. We developed an assay to examine how retinoschisin, which is secreted a distance away, reaches its inner retinal targets. We found that retinoschisin is preferentially taken up and carried into the inner retina from the retinal outer border (the photoreceptor side) by Müller cells (the main glial cells of the vertebrate retina). This transcytosis is disrupted by DL-alpha-aminoadipic acid, a Müller cell/glia-specific toxin. Our results suggest that glial uptake/transcytosis can provide an effective and precise alternative for distributing signaling molecules in the nervous system.