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PubMed2005

A combination drug therapy improves cognition and reverses gene expression changes in a mouse model of Huntington's disease.

Huntington's disease is a genetic disease caused by a single mutation. It is characterized by progressive movement, emotional and cognitive deficits. R6/2 mice transgenic for exon 1 of the HD gene with 150+ CAG repeats have a progressive neurological phenotype, including deterioration in cognitive function. The mechanism underlying the cognitive deficits in R6/2 mice is unknown, but dysregulated gene expression, reduced neurotransmitter levels and abnormal synaptic function are present before the cognitive decline becomes pronounced. Our goal here was to ameliorate the cognitive phenotype in R6/2 mice using a combination drug therapy (tacrine, moclobemide and creatine) aimed at boosting neurotransmitter levels in the brain. Treatment from 5 weeks of age prevented deterioration in two different cognitive tasks until at least 12 weeks. However, motor deterioration continued unabated. Microarray analysis of global gene expression revealed that many genes significantly up- or down-regulated in untreated R6/2 mice had returned towards normal levels after treatment, though a minority were further dysregulated. Thus dysregulated gene expression was reversed by the combination treatment in the R6/2 mice and probably underlies the observed improvements in cognitive function. Our study shows that cognitive decline caused by a genetic mutation can be slowed by a combination drug treatment, and gives hope that cognitive symptoms in HD can be treated.

Age Factors↗
PubMed2005

Cognitive disorders and neurogenesis deficits in Huntington's disease mice are rescued by fluoxetine.

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat encoding an extended polyglutamine tract in the huntingtin protein. Affected individuals display progressive motor, cognitive and psychiatric symptoms (including depression), leading to terminal decline. Given that transgenic HD mice have decreased hippocampal cell proliferation and that a deficit in neurogenesis has been postulated as an underlying cause of depression, we hypothesized that decreased hippocampal neurogenesis contributes to depressive symptoms and cognitive decline in HD. Fluoxetine, a serotonin-reuptake inhibitor commonly prescribed for the treatment of depression, is known to increase neurogenesis in the dentate gyrus of wild-type mouse hippocampus. Here we show that hippocampal-dependent cognitive and depressive-like behavioural symptoms occur in HD mice, and that the administration of fluoxetine produces a marked improvement in these deficits. Furthermore, fluoxetine was found to rescue deficits of neurogenesis and volume loss in the dentate gyrus of HD mice.

Age Factors↗
PubMed2006

Consequences of unilateral nigrostriatal denervation on the thalamostriatal pathway in rats.

The position of the caudal intralaminar nuclei within basal ganglia circuitry has largely been neglected in most studies dealing with basal ganglia function. During the past few years, there has been a growing body of evidence suggesting that the thalamic parafascicular nucleus in rodents (PF) exerts a multifaceted modulation of basal ganglia nuclei, at different levels. Our aim was to study the activity of the thalamostriatal pathway in rats with unilateral dopaminergic depletion. The experimental approach comprised first unilateral delivery of 6-OHDA in the medial forebrain bundle. Thirty days post-lesioning, animals showing a clear asymmetry were then subjected to bilateral injection of Fluoro-Gold (FG) within the striatum. Subsequently, expression of the mRNA encoding the vesicular glutamate transporter 2 (vGLUT2) was detected within thalamostriatal-projecting neurons (FG-labeled) by in situ hybridization and the results were confirmed by laser-guided capture microdissection microscopy followed by real-time PCR. The data showed that there was a marked neuronal loss restricted to PF neurons projecting to the dopamine-depleted striatum. Moreover, PF neurons innervating the dopamine-depleted striatum were intensely hyperactive. These neurons showed a marked increase on the expression of vGLUT2 mRNA as well as for the mRNA encoding the subunit I of cytochrome oxidase as compared with those neurons projecting to the striatum with normal dopamine content. Thus, the selective neurodegeneration of PF neurons innervating the striatum together with the increased activity of the thalamostriatal pathway coexist after nigrostriatal denervation.

Animals↗
PubMed2006

Neural progenitor cells engineered to secrete GDNF show enhanced survival, neuronal differentiation and improve cognitive function following traumatic brain injury.

We sought to evaluate the potential of C17.2 neural progenitor cells (NPCs) engineered to secrete glial cell line-derived neurotrophic factor (GDNF) to survive, differentiate and promote functional recovery following engraftment into the brains of adult male Sprague-Dawley rats subjected to lateral fluid percussion brain injury. First, we demonstrated continued cortical expression of GDNF receptor components (GFRalpha-1, c-Ret), suggesting that GDNF could have a physiological effect in the immediate post-traumatic period. Second, we demonstrated that GDNF over-expression reduced apoptotic NPC death in vitro. Finally, we demonstrated that GDNF over-expression improved survival, promoted neuronal differentiation of GDNF-NPCs at 6 weeks, as compared with untransduced (MT) C17.2 cells, following transplantation into the perilesional cortex of rats at 24 h post-injury, and that brain-injured animals receiving GDNF-C17.2 transplants showed improved learning compared with those receiving vehicle or MT-C17.2 cells. Our results suggest that transplantation of GDNF-expressing NPCs in the acute post-traumatic period promotes graft survival, migration, neuronal differentiation and improves cognitive outcome following traumatic brain injury.

Animals↗
PubMed2005

Reversal of non-hydroxy:alpha-hydroxy galactosylceramide ratio and unstable myelin in transgenic mice overexpressing UDP-galactose:ceramide galactosyltransferase.

The sphingolipids galactosylceramide and sulfatide are important for the formation and maintenance of myelin. Transgenic mice overexpressing the galactosylceramide synthesizing enzyme UDP-galactose:ceramide galactosyltransferase in oligodendrocytes display an up to four-fold increase in UDP-galactose:ceramide galactosyltransferase activity, which correlates with an increase in its products monogalactosyl diglyceride and non-hydroxy fatty acid-containing galactosylceramide. Surprisingly, however, we observed a concomitant decrease in alpha-hydroxylated galactosylceramide such that total galactosylceramide in transgenic mice was almost unaltered. These data suggest that UDP-galactose:ceramide galactosyltransferase activity does not limit total galactosylceramide level. Furthermore, the predominance of alpha-hydroxylated galactosylceramide appeared to be determined by the extent to which non-hydroxylated ceramide was galactosylated rather than by the higher affinity of UDP-galactose:ceramide galactosyltransferase for alpha-hydroxy fatty acid ceramide. The protein composition of myelin was unchanged with the exception of significant up-regulation of the myelin and lymphocyte protein. Transgenic mice were able to form myelin, which, however, was apparently unstable and uncompacted. These mice developed a progressive hindlimb paralysis and demyelination in the CNS, demonstrating that tight control of UDP-galactose:ceramide galactosyltransferase expression is essential for myelin maintenance.

Age Factors↗
PubMed2005

Serofendic acid prevents 6-hydroxydopamine-induced nigral neurodegeneration and drug-induced rotational asymmetry in hemi-parkinsonian rats.

Serofendic acid was recently identified as a neuroprotective factor from fetal calf serum. This study was designed to evaluate the neuroprotective effects of an intranigral microinjection of serofendic acid based on behavioral, neurochemical and histochemical studies in hemi-parkinsonian rats using 6-hydroxydopamine (6-OHDA). Rats were injected with 6-OHDA in the presence or absence of serofendic acid, or were treated with serofendic acid on the same lateral side, at 12, 24 or 72 h after 6-OHDA lesion. Intranigral injection of 6-OHDA alone induced a massive loss of tyrosine hydroxylase (TH)-immunopositive neurons in the substantia nigra pars compacta (SNpc). Either simultaneous or 12 h post-administration of serofendic acid significantly prevented both dopaminergic neurodegeneration and drug-induced rotational asymmetry. Immunoreactivities for oxidative stress markers, such as 3-nitrotyrosine (3-NT) and 4-hydroxy-2-nonenal (4-HNE), were markedly detected in the SNpc of rats injected with 6-OHDA alone. These immunoreactivities were markedly suppressed by the co-administration of serofendic acid, similar to the results in vehicle-treated control rats. In addition, serofendic acid inhibited 6-OHDA-induced alpha-synuclein expression and glial activation in the SNpc. These results suggest that serofendic acid protects against 6-OHDA-induced SNpc dopaminergic neurodegeneration in a rat model of Parkinson's disease.

Adrenergic Agents↗
PubMed2005

A gain-of-function mutation in the GABA receptor produces synaptic and behavioral abnormalities in the mouse.

In mammalian species, inhibition in the brain is mediated predominantly by the activation of GABAA receptors. We report here changes in inhibitory synaptic function and behavior in a mouse line harboring a gain-of-function mutation at Serine 270 (S270) in the GABAA receptor alpha1 subunit. In recombinant alpha1beta2gamma2 receptors, replacement of S270 by Histidine (H) results in an increase in sensitivity to gamma-aminobutyric acid (GABA), and slowing of deactivation following transient activation by saturating concentrations of GABA. Heterozygous mice expressing the S270H mutation are hyper-responsive to human contact, exhibit intention tremor, smaller body size and reduced viability. These mice also displayed reduced motor coordination, were hypoactive in the home cage, but paradoxically were hyperactive in a novel open field environment. Heterozygous knockin mice of both sexes were fertile but females failed to care for offspring. This deficit in maternal behavior prevented production of homozygous animals. Recordings from brain slices prepared from these animals revealed a substantial prolongation of miniature inhibitory postsynaptic currents (IPSCs) and a loss of sensitivity to the anesthetic isoflurane, in neurons that express a substantial amount of the alpha1 subunit. The results suggest that the biophysical properties of GABAA receptors are important in determining the time-course of inhibition in vivo, and suggest that the duration of synaptic inhibition is a critical determinant that influences a variety of behaviors in the mouse.

Amino Acid Substitution↗
PubMed2006

Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice.

Cholinergic neurons elaborate a hemicholinium-3 (HC-3) sensitive choline transporter (CHT) that mediates presynaptic, high-affinity choline uptake (HACU) in support of acetylcholine (ACh) synthesis and release. Homozygous deletion of CHT (-/-) is lethal shortly after birth (Ferguson et al. 2004), consistent with CHT as an essential component of cholinergic signaling, but precluding functional analyses of CHT contributions in adult animals. In contrast, CHT+/- mice are viable, fertile and display normal levels of synaptosomal HACU, yet demonstrate reduced CHT protein and increased sensitivity to HC-3, suggestive of underlying cholinergic hypofunction. We find that CHT+/- mice are equivalent to CHT+/+ siblings on measures of motor co-ordination (rotarod), general activity (open field), anxiety (elevated plus maze, light/dark paradigms) and spatial learning and memory (Morris water maze). However, CHT+/- mice display impaired performance as a result of physical challenge in the treadmill paradigm, as well as reduced sensitivity to challenge with the muscarinic receptor antagonist scopolamine in the open field paradigm. These behavioral alterations are accompanied by significantly reduced brain ACh levels, elevated choline levels and brain region-specific decreased expression of M1 and M2 muscarinic acetylcholine receptors. Our studies suggest that CHT hemizygosity results in adequate baseline ACh stores, sufficient to sustain many phenotypes, but normal sensitivities to physical and/or pharmacological challenge require full cholinergic signaling capacity.

Acetylcholine↗
PubMed2004

Spinophilin blocks arrestin actions in vitro and in vivo at G protein-coupled receptors.

Arrestin regulates almost all G protein-coupled receptor (GPCR)-mediated signaling and trafficking. We report that the multidomain protein, spinophilin, antagonizes these multiple arrestin functions. Through blocking G protein receptor kinase 2 (GRK2) association with receptor-Gbetagamma complexes, spinophilin reduces arrestin-stabilized receptor phosphorylation, receptor endocytosis, and the acceleration of mitogen-activated protein kinase (MAPK) activity following endocytosis. Spinophilin knockout mice were more sensitive than wild-type mice to sedation elicited by stimulation of alpha2 adrenergic receptors, whereas arrestin 3 knockout mice were more resistant, indicating that the signal-promoting, rather than the signal-terminating, roles of arrestin are more important for certain response pathways. The reciprocal interactions of GPCRs with spinophilin and arrestin represent a regulatory mechanism for fine-tuning complex receptor-orchestrated cell signaling and responses.

Adenosine↗
PubMed2005

Recovery of focal brain ischemia-induced behavioral dysfunction by intracerebroventricular injection of microglia.

The function of microglia in the brain parenchyma is not fully understood. Occlusion of the middle cerebral artery (MCA) and reperfusion caused behavioral dysfunction with massive neuronal loss in the rat cerebral cortex and striatum. When exogenous microglia were microinjected into the intracerebroventricle (i.c.v.) during MCA occlusion, focal ischemia-induced behavioral dysfunction was significantly inhibited. At that time, many microglia migrated into the ischemic lesion, and microglia-derived neuron-like cells were barely detectable. These results suggest that exogenous microglia protect against focal ischemia-induced neurodegeneration and improve behavioral dysfunction.

Animals↗
PubMed2000

Anticonvulsant effect of nimodipine alone and in combination with diazepam and phenytoin in a mouse model of status epilepticus.

The effect of nimodipine alone and in combination with diazepam or phenytoin was tested in the electroshock-induced mouse model of status epilepticus. Status epilepticus was induced by transauricular electrical stimulation with a stimulus of 15 mA at 0.5, 3, 10, 20 and 30 min, starting half an hour after intraperitoneal administration of vehicle/drug. The median effective doses of diazepam and phenytoin alone and in combination with a fixed dose of nimodipine (24 mg/kg) was calculated. The ED50s of diazepam and phenytoin were found to be 10.5 and 9 mg/kg, respectively. When nimodipine was combined with diazepam or phenytoin, the ED50 values decreased to 3.77 mg/kg and 7.15 mg/kg, respectively. The severity of seizures was also decreased by combination with nimodipine as compared to diazepam and phenytoin given alone. To study the effect of nimodipine on psychomotor impairments produced by diazepam and phenytoin three tests were performed: rotarod, behavioral despair and hole board. Nimodipine did not show protective effects on its own but potentiated the anticonvulsant effects of diazepam and phenytoin. Furthermore, the combination of nimodipine with diazepam and phenytoin produced lesser impairment of psychomotor functions.

Animals↗
PubMed2004

Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, polyglutamine-induced neurodegenerative disorder that results in loss of motor coordination caused primarily by a disruption of cerebellar Purkinje cell function. In this study, we developed a conditional SCA1 mouse model to examine whether stopping expression of mutant ataxin-1 alters the disease phenotype. After cessation of SCA1[82Q] transgene expression, mutant ataxin-1, including that in nuclear inclusions, was cleared rapidly from Purkinje cells. At an early stage of disease, Purkinje cell pathology and motor dysfunction were completely reversible. After halting SCA1 expression at later stages of disease, only a partial recovery was seen. Interestingly, restoration of the ability to perform a complex motor task, the accelerating Rotarod, correlated with localization of mGluR1alpha to the Purkinje cell-parallel fiber synapse. These results show that the progression of SCA1 pathogenesis is dependent on the continuous expression of mutant ataxin-1. Of note, even at a late stage of disease, Purkinje cells retain at least some ability to repair the damage caused by mutant ataxin-1.

Animals↗
PubMed2004

CNS myelin paranodes require Nkx6-2 homeoprotein transcriptional activity for normal structure.

Homeodomain proteins play critical roles during development in cell fate determination and proliferation, but few studies have defined gene regulatory networks for this class of transcription factors in differentiated cells. Using a lacZ-knock-in strategy to ablate Nkx6-2, we find that the Nkx6-2 promoter is active embryonically in neuroblasts and postnatally in oligodendrocytes. In addition to neurological deficits, we find widespread ultrastructural abnormalities in CNS white matter and aberrant expression of three genes encoding a paranodal microtubule destabilizing protein, stathmin 1, and the paranodal cell adhesion molecules neurofascin and contactin. The involvement of these downstream proteins in cytoskeletal function and cell adhesion reveals mechanisms whereby Nkx6-2 directly or indirectly regulates axon- glial interactions at myelin paranodes. Nkx6-2 does not appear to be the central regulator of axoglial junction assembly; nonetheless, our data constitute the first evidence of such a regulatory network and provide novel insights into the mechanism and effector molecules that are involved.

Animals↗
PubMed2005

Deficits in experience-dependent cortical plasticity and sensory-discrimination learning in presymptomatic Huntington's disease mice.

Huntington's disease (HD) is one of a group of neurodegenerative diseases caused by an expanded trinucleotide (CAG) repeat coding for an extended polyglutamine tract. The disease is inherited in an autosomal dominant manner, with onset of motor, cognitive, and psychiatric symptoms typically occurring in midlife, followed by unremitting progression and eventual death. We report here that motor presymptomatic R6/1 HD mice show a severe impairment of somatosensory-discrimination learning ability in a behavioral task that depends heavily on the barrel cortex. In parallel, there are deficits in barrel-cortex plasticity after a somatosensory whisker-deprivation paradigm. The present study demonstrates deficits in neocortical plasticity correlated with a specific learning impairment involving the same neocortical area, a finding that provides new insight into the cellular basis of early cognitive deficits in HD.

Age Factors↗
PubMed2003

The rotarod.

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Animal Welfare↗
PubMed1990

Toxic effects of acute exposure to particular xylene isomers in animals.

The effect of exposure to particular xylene isomers at a concentration of 3000 ppm on rotarod performance in rats and the respiratory rate in mice was investigated. Rotarod performance was tested in rats immediately after termination of a 6-hour exposure, and the respiratory rate in mice was recorded during a short 6 minute exposure to individual xylene isomers. In both rats and mice the toxic effects of exposure to ortho- and meta-xylene were more pronounced than that of para-xylene.

Acute Disease↗
PubMed1983

Genetics of nicotine response in four inbred strains of mice.

The effects of nicotine on five behavioral and physiological measures were determined in four inbred mouse strains (BALB, C57BL, DBA and C3H). In addition, the binding characteristics of nicotine and alpha-bungarotoxin, two ligands which appear to label different nicotinic receptors, were measured in seven discrete brain regions, as well as in whole brain. A number of differences in response to nicotine were found among the four inbred strains. Whereas nicotine depressed open-field activity of BALB, C57BL and DBA mice in a dose-dependent manner, low doses of nicotine increased locomotor activity in C3H mice. The doses of nicotine tested reduced Rotarod performance in DBA and C57BL mice but not in C3H and BALB mice. All four strains displayed a dose-dependent decrease in body temperature after nicotine administration. The BALB mice were more sensitive to the drug than were the C3H, whereas the effects on C57BL and DBA mice were intermediate. All four strains showed a transient increase in respiration only after a high (2.0 mg/kg) nicotine dose. No dose of nicotine was found to have an effect on the startle response after auditory stimulation in three of the strains; only the C3H mice exhibited enhanced startle after nicotine was administered. Differences in DL-[ 3H ]nicotine binding among the seven brain regions were noted in each strain, but no differences among strains were observed. The IC50 values for inhibition of this binding by nicotine did not differ among brain regions within any strain or within any region among strains. Similarly, nicotine inhibited alpha-[125I]bungarotoxin binding with equal potency in all brain regions of each of the four strains; however, the binding of this ligand was significantly lower in the midbrain and hippocampus of DBA mice than it was in these regions in the other three strains. Thus, genetic factors influence response to nicotine, but variation in response is not easily explained by differences in brain nicotinic receptors.

Animals↗
PubMed2000

Does status epilepticus influence the motor development of immature rats?

PURPOSE: To study the effect of severe status epilepticus (SE) on the motor development of rats. METHODS: SE was induced in 12-day-old rats (P12 group) and 25-day-old rats (P25 group) using the lithium-pilocarpine model. Seizures were interrupted after 2 hours by paraldehyde with an intraperitoneal dose of 0.3 or 0.6 mL/kg, respectively. Starting 3 days after SE, all animals were repeatedly exposed to a battery of motor and behavioral tests, including the bar-holding test, rotarod test, and open field test. RESULTS: In P12 animals, motor impairment occurred 2 months after SE, when significantly worse performance in the rotarod test was found. No difference between controls and experimental rats was found in any other test used. In contrast, P25 animals were significantly poorer in the bar-holding test from postnatal day 34 until adulthood. In open field study, P25 rats were found to be hyperactive during the whole period of testing, whereas P12 animals exhibited an initial period of hypoactivity (in the first test) that was replaced by hyperactivity that lasted until 2 months of age. In the last test performed at the age of 98 days, experimental P12 animals were again less active than age-matched controls. CONCLUSIONS: Animals of both age groups exhibited permanent changes of motor performance; however, both the pattern and the time course of these changes was related to age when SE was elicited.

Age Factors↗