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Biomedical subjects

A Jennifer Morton

Publications and source records attributed to A Jennifer Morton.

At least 19 recordsLinked to original sources
PubMed2006

Early motor development is abnormal in complexin 1 knockout mice.

Complexin I expression is dysregulated in a number of neurological diseases including schizophrenia and depression. Adult complexin 1 knockout (Cplx1(-/-)) mice are severely ataxic and show deficits in exploration and emotional reactivity. Here, we evaluated early behavioural development of Cplx1(-/-) mice. Cplx1(-/-) mice showed marked abnormalities. They develop ataxia by post-natal day 7 (P7), and by P21 show marked deficits in tasks requiring postural skills and complex movement. These deficits are consistent with abnormalities in sensory and motor development found in infants that develop schizophrenia in later life. A role for complexin I depletion should be considered in diseases where deficits in early sensory and motor development exist, such as autism and schizophrenia.

Adaptor Proteins, Vesicular Transport↗
PubMed2006

Systemic administration of Congo red does not improve motor or cognitive function in R6/2 mice.

Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no treatment. Prior to the onset of symptoms, abnormal protein aggregates (inclusions) are found in neurons in humans and R6/2 mice. It has been suggested that the progression of HD can be slowed or prevented by disruption of the aggregation process. In agreement with this, it has been reported that systemic treatment of R6/2 mice with Congo red caused a reduction in numbers of striatal inclusions and an improvement in motor symptoms and survival [Sanchez, I., Mahlke, C., Yuan, J., 2003. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373-379]. Here we attempted to replicate this study. We extended the experiment to include measurement of the effects of Congo red on cognitive function in R6/2 mice. Congo red treatment failed to ameliorate either motor or cognitive deficits in R6/2 mice. We suggest that this is due to the inability of Congo red to cross the blood-brain barrier. Since it does not improve the behavioural deterioration that is a key feature of HD, Congo red is unlikely to be useful as a therapy for HD.

Animals↗
PubMed2006

Limbic neurogenesis/plasticity in the R6/2 mouse model of Huntington's disease.

Huntington's disease is an inherited neurodegenerative condition characterized by movement disorders, and mood and cognitive disturbance. Mammalian neurogenesis persists into adulthood in the subventricular zone and dentate gyrus of the hippocampus. Neurogenesis is abnormal in the dentate gyrus in the R6/2 transgenic mouse model of Huntington's disease. We have now found that the number of immature neurons (doublecortin-positive cells) is markedly reduced in the piriform and insular cortex but not in the temporal germinal layer or caudal subventricular zone of R6/2 mice. Furthermore, numbers of such cells were unaltered in response to seizures in both wild-type and R6/2 mice. These results support the possibility that impaired neurogenesis and/or plasticity could contribute to cognitive and psychiatric impairments in Huntington's disease.

Aging↗
PubMed2006

Calcineurin inhibitors cause an acceleration of the neurological phenotype in a mouse transgenic for the human Huntington's disease mutation.

Calcineurin (CaN) is a Ca(2+)- and calmodulin-dependent protein serine-threonine phosphatase that is thought to play an important role in the neuronal response to changes in the intracellular Ca(2+) concentration. CaN has been implicated in numerous physiological processes including learning and memory. Decreases in CaN expression are thought to be responsible for some of the pathological features seen in brain ischemia, Down's syndrome and Alzheimer's disease. In this study, we examined the possibility of CaN playing a role in the progressive neurological phenotype of the R6/2 mouse of Huntington's disease. We studied the effects of the CaN inhibitors cyclosporin A and FK506 on the progressive neurological phenotype in the R6/2 mouse. We found that an immunosuppressive dose of both drugs dramatically accelerated the main features of the neurological phenotype in R6/2 mice. This was unlikely to be due solely to the immunosuppressive action of these drugs, since treatment with cyclophosphamide, an immunosuppressant drug with a mechanism of action that is not mediated via CaN, did not have deleterious effects on the R6/2 mouse. If anything, cyclophosphamide improved the neurological symptoms in the R6/2 mice. Together, our data suggest a central role for CaN in the deleterious phenotype of the R6/2 mouse. Treatments aimed at preventing the loss of CaN or stimulating its function may be beneficial in the treatment of HD.

Analysis of Variance↗
PubMed2005

Abnormalities of neurogenesis in the R6/2 mouse model of Huntington's disease are attributable to the in vivo microenvironment.

Huntington's disease (HD) is an autosomal dominant neurodegenerative condition characterized by movement disorders, psychiatric disturbance, and cognitive decline. There are no treatments to halt or reverse the disease. Mammalian neurogenesis persists into adulthood in the subventricular zone (SVZ) and dentate gyrus (DG) of the hippocampus. In 2001, our laboratory published the hypothesis that neurogenesis is impaired in neurodegenerative diseases and that this may contribute to disease progression. Since then, it has been shown that neurogenesis is reduced in the DG of transgenic HD mice but increased in the SVZ of HD patients. We sought to characterize neurogenesis further. We found that, in the DG of the transgenic R6/2 mouse model of HD, newborn cell proliferation and morphology, but not differentiation or survival, was compromised. In R6/2 mice, neurogenesis failed to upregulate in the DG in response to seizures. Basal SVZ neurogenesis was similar between R6/2 mice and their wild-type littermates. There was no difference in the in vitro growth of adult neural precursor cells (NPCs) between genotypes. These results suggest that abnormal neurogenesis in the R6/2 mouse is not attributable to an intrinsic impairment of the NPC itself but is attributable to the environment in which the cell is located.

Aging↗
PubMed2005

Atypical diabetes associated with inclusion formation in the R6/2 mouse model of Huntington's disease is not improved by treatment with hypoglycaemic agents.

The R6/2 transgenic mouse model of Huntington's disease (HD) develops a progressive neurological phenotype that involves severe motor and cognitive dysfunctions. Although not a cardinal sign, diabetes has been described in R6/2 mice. It is not clear, however, whether the diabetes contributes to the HD-like phenotype of R6/2 mice. In our study we found that the severity of diabetes in R6/2 mice was associated with the progressive formation of ubiquinated inclusions in pancreatic beta cells. Diabetes is dissociated from early motor and cognitive dysfunctions and did not correlate with motor impairment and survival of R6/2 mice. However, chronic behavioural testing (at a level higher than that which is reported to improve several aspects of the R6/2 phenotype) exacerbated the onset of diabetes. Pharmacological treatment of the diabetes was attempted using two oral hypoglycaemic agents commonly used by diabetics. The mice responded acutely to glibenclamide (which induces exocytosis of insulin) but not to rosiglitazone (which induces sensitization to insulin). This supports the suggestion that the diabetes in R6/2 mice is caused by an impairment in insulin release rather than insulin insensitivity. However, chronic treatment with these hypoglycaemic agents had no effect on either the course of the diabetes or the disease in R6/2 mice.

Administration, Oral↗
PubMed2005

Profound ataxia in complexin I knockout mice masks a complex phenotype that includes exploratory and habituation deficits.

Complexins are presynaptic proteins that bind to the SNARE complex where they modulate neurotransmitter release. A number of studies report changes in complexins in psychiatric (schizophrenia and depression) and neurodegenerative disorders (Huntington's disease, Wernicke's encephalopathy and Parkinson's disease). Here, we characterize the behavioural phenotype of Cplx1 knockout (Cplx1-/-) mice. Cplx1-/- mice develop a strong ataxia in the absence of cerebellar degeneration. Although originally reported to die within 2-4 months after birth, when reared using an enhanced feeding regime, these mice survive normally (i.e. >2 years). Cplx1-/- mice show pronounced deficits in motor coordination and locomotion including abnormal gait, inability to run or swim, impaired rotarod performance, reduced neuromuscular strength, dystonia and resting tremor. Although the abnormal motor phenotype dominates their overt symptoms, Cplx1-/- mice also show other behavioural deficits, particularly in complex behaviours. They have deficits in grooming and rearing behaviour and show reduced exploration in several different paradigms. They also show deficits in tasks reflecting emotional reactivity. They fail to habituate to confinement and show a 'panic' response when exposed to water. The abnormalities seen in the behaviour of Cplx1-/- mice reflect those predicted from the distribution of complexin I in the brain. Our data show that complexin I is essential not only for normal motor function in mice, but also for normal performance of other complex behaviours. These results support the idea that altered expression of complexins in disease states may contribute to the symptomatology of disorders in which they are dysregulated.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Syncollin is required for efficient zymogen granule exocytosis.

Syncollin is a 13 kDa protein that is present in the exocrine pancreas, where the majority of the protein is tightly attached to the luminal surface of the zymogen granule membrane. We have addressed the physiological role of syncollin by studying the phenotype of syncollin KO (knockout) mice. These mice show pancreatic hypertrophy and elevated pancreatic amylase levels. Further, secretagogue-stimulated amylase release from pancreatic lobules of syncollin KO mice was found to be reduced by about 45% compared with wild-type lobules, and the delivery of newly synthesized protein to zymogen granules was delayed, indicating that the mice have a pancreatic secretory defect. As determined by two-photon imaging, the number of secretagogue-stimulated exocytotic events in acini from syncollin KO mice was reduced by 50%. This reduction was accounted for predominantly by a loss of later, 'secondary' fusion events between zymogen granules and other granules that had already fused with the plasma membrane. We conclude that syncollin is required for efficient exocytosis in the pancreatic acinar cell, and that it plays a particularly important role in compound exocytosis.

Amylases↗
PubMed2005

Disintegration of the sleep-wake cycle and circadian timing in Huntington's disease.

Sleep disturbances in neurological disorders have a devastating impact on patient and carer alike. However, their pathological origin is unknown. Here we show that patients with Huntington's disease (HD) have disrupted night-day activity patterns. This disruption was mirrored in a transgenic model of HD (R6/2 mice) in which daytime activity increased and nocturnal activity fell, eventually leading to the complete disintegration of circadian behavior. The behavioral disturbance was accompanied by marked disruption of expression of the circadian clock genes mPer2 and mBmal1 in the suprachiasmatic nuclei (SCN), the principal circadian pacemaker in the brain. The circadian peak of expression of mPer2 was prematurely truncated, and the mRNA levels of mBmal1 were attenuated and failed to exhibit a significant circadian oscillation. Circadian cycles of gene expression in the motor cortex and striatum, markers of behavioral activation in wild-type mice, were also suppressed in the R6/2 mice, providing a neural correlate of the disturbed activity cycles. Increased daytime activity was also associated with reduced SCN expression of prokineticin 2, a transcriptional target of mBmal1 encoding a neuropeptide that normally suppresses daytime activity in nocturnal mammals. Together, these molecular abnormalities could explain the pathophysiological changes in circadian behavior. We propose that circadian sleep disturbances are an important pathological feature of HD, that they arise from pathology within the SCN molecular oscillation, and that their treatment will bring appreciable benefits to HD patients.

Adult↗
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

A similar impairment in CA3 mossy fibre LTP in the R6/2 mouse model of Huntington's disease and in the complexin II knockout mouse.

Complexin II is reduced in Huntington's disease (HD) patients and in the R6/2 mouse model of HD. Mice lacking complexin II (Cplx2-/- mice) show selective cognitive deficits that reflect those seen in R6/2 mice. To determine whether or not there is a common mechanism that might underlie the cognitive deficits, long-term potentiation (LTP) was examined in the CA3 region of hippocampal slices from R6/2 mice and Cplx2-/- mice. While associational/commissural (A/C) LTP was not significantly different, mossy fibre (MF) LTP was significantly reduced in slices from R6/2 mice and Cplx2-/- mice compared with wild-type (WT) and Cplx2+/+ control mice. MF field excitatory postsynaptic potentials (fEPSPs) in response to paired stimuli were not significantly different between control mice and R6/2 or Cplx2-/- mice, suggesting that MF basal glutamate release is unaffected. Forskolin (30 microm) caused an increase in glutamate release at MF synapses in slices from R6/2 mice and from Cplx2-/- mice that was not significantly different from that seen in control mice, indicating that the capacity for increased glutamate release is not diminished. Thus, R6/2 mice and Cplx2-/- mice have a common selective impairment of MF LTP in the CA3 region. Together, these data suggest that complexin II is required for MF LTP, and that depletion of complexin II causes a selective impairment in MF LTP in the CA3 region. This impairment in MF LTP could contribute to spatial learning deficits observed in R6/2 and Cplx2-/- mice.

2-Amino-5-phosphonovalerate↗
PubMed2004

Differential messenger RNA expression of complexins in mouse brain.

Complexins (CPLXs) are small isomeric proteins that bind to the soluble NSF-attachment protein receptor (SNARE) complex and modulate neurotransmitter release. Two isoforms of CPLX exist in the brain, CPLXI and CPLXII. These are differentially distributed in the cortex and cerebellum, with CPLXI found in axosomatic terminals and CPLXII in axodendritic terminals. Since in cortex and cerebellum axosomatic terminals are inhibitory and axodendritic terminals are excitatory, it has been assumed that CPLXI modulates inhibitory and CPLXII modulates excitatory transmitter release. Here we used in situ hybridisation to study the mRNA distribution of CPLXI and CPLXII in mouse brain. We show that while CPLXs are expressed in distinct cell populations, they do not segregate with either particular neurotransmitters, or different classes of transmitter action. For example, while CPLXII is the dominant isoform in the output (glutamatergic excitatory) neurons of the cortex, it is also the dominant isoform in medium spiny (GABAergic inhibitory) neurons of the striatum. We suggest that the functional role of CPLXs depends not only on the identity of the neurotransmitter, but also upon the circuitry connecting the neurons in which they are expressed. Thus, the predominant expression of CPLXII in neurons of the basal ganglia and cortex suggests a role in cognition, emotional behaviour and control of voluntary movement, while the pattern of CPLXI expression suggests a primary role in motor learning programs and sensory processing.

Adaptor Proteins, Vesicular Transport↗
PubMed2004

Regional and progressive changes in brain expression of complexin II in a mouse transgenic for the Huntington's disease mutation.

Changes in mRNA expression of soluble NSF-attachment protein receptors (SNAREs) and SNARE-associated proteins have been shown to occur in a number of disorders such as schizophrenia, Alzheimer's disease and Parkinson's disease. We have shown previously that there is a decrease in protein levels of the SNARE-associated protein, complexin II (CPLXII) in Huntington's disease brain and in the R6/2 mouse model of Huntington's disease. In the current study, we used quantitative in situ hybridisation to examine mRNA expression of SNAREs (25 kDa synaptosome-associated protein (SNAP-25), syntaxin-1A and synaptobrevin-2) and SNARE-associated proteins (alpha-SNAP, CPLXI and CPLXII) in brain of R6/2 mice and their wild type littermates between 3 and 15 weeks of age. We found an early and progressive decrease of CPLXII expression in R6/2 mice brains. In contrast, no changes in SNARE expression were seen in R6/2 brains compared with wild type brain. Further, while decreased expression of alpha-SNAP and CPLXI was seen, this was not until 15 weeks of age and even then the changes were small. We suggest that downregulation of expression of mRNA encoding SNARE-associated proteins, first CPLXII and later CPLXI and alpha-SNAP, contributes to the progressive neuropathology of the R6/2 mouse model of Huntington's disease.

Adaptor Proteins, Vesicular Transport↗
PubMed2004

Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation.

Huntington's disease (HD) is a neurodegenerative disorder with complex symptoms dominated by progressive motor dysfunction. Skeletal muscle atrophy is common in HD patients. Because the HD mutation is expressed in skeletal muscle as well as brain, we wondered whether the muscle changes arise from primary pathology. We used R6/2 transgenic mice for our studies. Unlike denervation atrophy, skeletal muscle atrophy in R6/2 mice occurs uniformly. Paradoxically however, skeletal muscles show age-dependent denervation-like abnormalities, including supersensitivity to acetylcholine, decreased sensitivity to mu-conotoxin, and anode-break action potentials. Morphological abnormalities of neuromuscular junctions are also present, particularly in older R6/2 mice. Severely affected R6/2 mice show a progressive increase in the number of motor endplates that fail to respond to nerve stimulation. Surprisingly, there was no constitutive sprouting of motor neurons in R6/2 muscles, even in severely atrophic muscles that showed other denervation-like characteristics. In fact, there was an age-dependent loss of regenerative capacity of motor neurons in R6/2 mice. Because muscle fibers appear to be released from the activity-dependent cues that regulate membrane properties and muscle size, and motor axons and nerve terminals become impaired in their capacity to release neurotransmitter and to respond to stimuli that normally evoke sprouting and adaptive reinnervation, we speculate that in these mice there is a progressive dissociation of trophic signalling between motor neurons and skeletal muscle. However, irrespective of the cause, the abnormalities at neuromuscular junctions we report here are likely to contribute to the pathological phenotype in R6/2 mice, particularly in late stages of the disease.

Acetylcholine↗
PubMed2003

Chronic lithium chloride treatment has variable effects on motor behaviour and survival of mice transgenic for the Huntington's disease mutation.

Expression of the Huntington's disease (HD) mutation in mice (R6/2 line) causes a progressive neurological phenotype that includes deterioration of motor function resembling that seen in HD. The current study sought to determine whether or not chronic treatment of R6/2 mice with lithium chloride would have an effect on the progression of the phenotype, in light of lithium's reported neuroprotective and anti-depressive properties. Treatment began either before or after the onset of symptoms. Chronic treatment with lithium caused a significant improvement in rotarod performance when treatment was started post- but not pre-symptomatically. There was no overall effect on survival in either group, but further analysis revealed that in the post-symptomatic group, mice could be assigned to one of two distinct groups, depending on the effects of lithium. One subgroup of mice lost weight faster, died earlier and showed rotarod performance similar to the vehicle-treated controls. The other subgroup lost weight at a normal rate, died at a similar age, but showed greatly improved motor performance compared to controls. The improvement in rotarod performance suggests that lithium may improve motor symptoms as well as depression in some HD patients.

Aging↗
PubMed2003

Complexin II is essential for normal neurological function in mice.

Complexins (CPLXs) are modulators of synaptic vesicle release. At 1 year of age, CPLXII knockout (KO) mice appear normal. However, behavioral testing reveals underlying deficits of motor and cognitive function in these mice. We found motor deficits on the rotarod, and learning deficits in the Morris water maze (both acquisition and reversal) and the two-choice swim tank (reversal). The reversal learning deficits are particularly noticeable, being present from the earliest time of testing, when most other behaviors are normal. CPLXII KO mice also fail to develop adult patterns of exploratory behavior in the open field and show deficits in interactive grooming behaviors. The behavioral deficits worsen with age. For example, while rotarod performance is normal until 10 weeks, it is impaired from 24 weeks onwards. Similarly, deficits in spatial learning in the Morris water maze are mild at 8 weeks, but pronounced by 1 year of age. The deficits seen in CPLXII KO mice are not due to physical weakness, since their ability to run, swim and grip is unimpaired. Rather, the mice appear to have deficits of higher function. The deficits seen in CPLXII KO mice are strikingly similar to those seen in the R6/2 model of Huntington's disease (HD) where a progressive depletion of CPLXII is seen. This suggests that depletion of CPLXII contributes to cognitive abnormalities in R6/2 mice. Given that decreased expression of CPLXII is seen in HD and schizophrenic patients, a role for CPLXII depletion should be considered in other diseases where motor, cognitive and psychiatric symptoms co-exist.

Adaptor Proteins, Vesicular Transport↗
PubMed2003

Expression of mutant huntingtin blocks exocytosis in PC12 cells by depletion of complexin II.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the HD gene. We reported recently that complexin II, a protein involved in neurotransmitter release, is depleted from both the brains of mice carrying the HD mutation and from the striatum of post mortem HD brains. Here we show that this loss of complexin II is recapitulated in PC12 cells expressing the HD mutation and is accompanied by a dramatic decline in Ca2+-triggered exocytosis of neurotransmitter. Overexpression of complexin II (but not complexin I) rescued exocytosis, demonstrating that the decline in neurotransmitter release is a direct consequence of complexin II depletion. Complexin II depletion in the brain may account for some of the abnormalities in neurotransmission associated with HD.

Adaptor Proteins, Vesicular Transport↗