Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Transgenes”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,063 records · Page 59Linked to original sources
PubMed1991

Characterization of O6-methylguanine-DNA methyltransferase in transgenic mice introduced with the E. coli ada gene.

The characteristics of O6-methylguanine-DNA methyltransferase (O6-MTase) produced in transgenic mice, in which the introduced E. coli ada gene was expressed under the control of the metallothionein promoter, were investigated. Liver extracts from transgenic homozygotes showed approximately 3 times the control activity, a marked increase of up to about 8 times the non-transgenic control levels being observed 10 h after zinc treatment. Examination of the substrate specificity of the enzyme revealed that the activity in the transgenic mice is due to the introduced foreign gene. The enzyme possessed methylphosphotriester-DNA methyltransferase as well as O6-MTase, characteristic of the E. coli Ada protein. Comparison of differences in biological response between transgenic and non-transgenic mice after treatment with the alkylating carcinogen methylnitrosourea (MNU) at various doses revealed transgenic mice to be more capable of repairing O6-MTase activity, only showing signs of exhaustion at very high levels of exposure. In non-transgenic mice, on the other hand, the basal level of O6-MTase was low, and the activity was hardly detectable when the animals were treated with MNU.

Animals↗
PubMed1994

Characterization of primary cultures of chondrocytes from type II collagen/beta-galactosidase transgenic mice.

Studies on the function of extracellular matrix components of cartilages and on chondrocyte-specific regulatory mechanisms will benefit from approaches in which transgenic mice and cell cultures will complement each other. We therefore established and extensively characterized primary cultures of mouse chondrocytes isolated from rib growth plates of newborn mice harboring a transgene in which type II collagen gene regulatory sequences were driving expression of an E. coli beta-galactosidase reporter gene. Primary chondrocytes expressed a fully differentiated phenotype in monolayer culture, producing mRNAs for the collagen types II, IX and X, and for the transgene. Transgenic cells also synthesized high levels of E. coli beta-galactosidase, easily quantifiable and also detectable in individual cells by X-gal staining. When chondrocytes were isolated from transgenic mice in which beta-galactosidase was fused to the product of the neomycin resistance gene, they displayed resistance to G418. After one to two weeks in culture, chondrocytes progressively lost expression of the transgenes, in parallel with that of cartilage-specific genes, and started expressing high levels of type I collagen RNA. The use of transgenic chondrocytes allowed us to easily score phenotypic changes by assaying beta-galactosidase activity and neomycin resistance. Cultures of mouse chondrocytes, such as those reported here, should also help characterize biochemically the phenotypes of other transgenic mice in studies of genetic diseases of cartilages and of mechanisms involved in chondrogenesis.

Animals↗
PubMed2005

Generation and characterization of a transgenic mouse model with hepatic expression of human CYP2A6.

The aim of this study was to prepare and characterize a transgenic mouse model in which CYP2A6, a human P450 enzyme, is expressed specifically in the liver. CYP2A6, which is mainly expressed in human liver, is active toward many xenobiotics. Our transgene construct contained the mouse transthyretin promoter/enhancer, a full-length CYP2A6 cDNA, and a downstream neomycin-resistance gene for positive selection in embryonic stem cells. Hepatic expression of the CYP2A6 transgene was demonstrated by immunoblotting, whereas tissue specificity of CYP2A6 expression was confirmed by RNA-PCR. The transgenic mouse was further characterized after being backcrossed to the B6 strain for six generations. Hepatic microsomes from homozygous transgenic mice had activities significantly higher than those of B6 mice toward coumarin. The in vivo activity of transgenic CYP2A6 was also determined. Systemic clearance of coumarin was significantly higher in the transgenic mice than in B6 controls, consistent with the predicted role of CYP2A6 as the major coumarin hydroxylase in human liver. The CYP2A6-transgenic mouse model should be valuable for studying the in vivo function of this polymorphic human enzyme in drug metabolism and chemical toxicity.

Animals↗
PubMed2004

Human keratin 14 driven HPV 16 E6/E7 transgenic mice exhibit hyperkeratinosis.

Human papillomavirus type 16 (HPV16) has been known as a major causative factor for the development of uterine cervical carcinomas. To investigate the in vivo activity of HPV16 expressed in squamous epithelia, transgenic mice harboring HPV16 E6/E7 with human keratin 14 (hK14) promoter were generated. Grossly, hK14 driven HPV16 E6/E7 transgenic mice exhibited multiple phenotypes, including wrinkled skin that was apparent prior to the appearance of hair in neonates, thickened ears, and loss of hair in adults. Transgenic mice with phenotype exhibiting severe wrinkled skin and a lack of hair growth died at the age of 3-4 weeks. Histological analysis revealed that in transgenic mice survived beyond the initial 3-4 weeks, HPV16 E6/E7 causes epidermal hyperplasia in multiple transgenic lineages with high incidence of transgene penetration. This epithelial hyperplasia was characterized by an expansion of the proliferating compartment and keratinocytes, and was associated with hyperkeratosis. Such activities were significantly higher in the skin of transgenic mice than that of the normal mice. Thus, these transgenic mice appeared to be useful for the expression of HPV16 E6/E7 gene and subsequent analysis on hyperkeratosis.

Animals↗
PubMed2005

Characterization of a double (amyloid precursor protein-tau) transgenic: tau phosphorylation and aggregation.

A double transgenic mouse expressing the amyloid precursor protein, bearing the Swedish mutations, and expressing tau protein containing three of the mutations present in frontotemporal dementia linked to chromosome 17 (FTDP-17), has been characterized. In the double transgenic mouse an increase in tau phosphorylation at serine S262 and S422 was observed compared with that found in simple transgenic mice. The phosphorylation at S262 was also found, in a much lower level, in the single transgenic mouse expressing amyloid precursor protein (APP), and it was absent in that overexpressing tau variant. Additionally, in the double transgenic mouse a slight increase in the amount of sarkosyl insoluble tau polymers was observed in comparison with that found in single transgenic tau mouse. Also, wider tau filaments were found in the double transgenic mouse compared with those found in the single transgenic mouse. Our results suggest that beta-amyloid peptide could facilitate the phosphorylation of tau at a site not directed by proline, such as serine 262, and that modification could facilitate tau aberrant aggregation. Also, they suggest that different types of tau filamentous polymers can occur in different mouse models for tauopathies, like those used for Alzheimer's disease or FTDP-17.

Amyloid beta-Peptides↗
PubMed2005

Male transgenic glycine receptor alpha1 (S267Q) mutant mice display a hyperekplexia-like increase in acoustic startle responses.

Glycine receptors (GlyR) are ligand-gated ion channels that inhibit neurotransmission in the spinal cord and brainstem, and mutations in GlyR can cause the human disease hyperekplexia, which is characterized by elevated startle responses. Recently, the GlyR alpha1S267Q mutation was shown to disrupt normal GlyR function, and knock-in mice harboring this mutation displayed profoundly increased acoustic startle responses and reduced glycine-stimulated the chloride flux [Findlay, G.S., Phelan, R., Roberts, M.T., Homanics, G.E., Bergeson, S.E., Lopreato, G.F., Mihic, S.J., Blednov, Y.A., Harris, R.A. 2003. Glycine receptor knock-in mice and hyperekplexia: comparisons with the null mutant. J Neurosci 23, 8051-8059.]. In this study, a transgenic mouse model expressing this S267Q mutation was evaluated using similar techniques to determine if these mice are similarly affected. Male transgenic mice displayed increased acoustic startle responses. However, decreases in glycine-stimulated strychnine-sensitive radioactive chloride (36Cl-) uptake were not observed in spinal cord and brainstem synaptoneurosomes from transgenic mice. No changes in habituation or prepulse inhibition of startle responses or spontaneous locomotion in response to taurine were observed as a result of presence of the transgene. Consistent with previous studies using immunoblotting and strychnine binding [Findlay, G.S., Wick, M.J., Mascia, M.P., Wallace, D., Miller, G.W., Harris, R.A., Blednov, Y.A. 2002. Transgenic expression of a mutant glycine receptor decreases alcohol sensitivity of mice. J Pharmacol Exp Ther 300, 526-534.], the glycine-stimulated strychnine-sensitive chloride flux of cortical microsacs in transgenic mice confirmed the ectopic expression of transgenic GlyR. These results support both the idea that transgenic expression of the S267Q mutation produces a less dramatic phenotype as compared to the knock-in mouse model as well as the idea that the in vivo acoustic startle test (as compared to the in vitro chloride flux assay) is particularly sensitive to disruptions in GlyR function.

Animals↗
PubMed2003

Regeneration of transgenic skeletal muscles with altered timing of expression of the basic helix-loop-helix muscle regulatory factor MRF4.

In regenerating muscle cells, muscle regulatory factor (MRF) 4 is normally the last of the four MRFs to be expressed. To analyze how the timing of MRF4 expression affects muscle regeneration, we compared regeneration after local freeze injury of muscles from wild-type mice with muscles from transgenic mice in which MRF4 expression was under control of an approximately 1.6-kb fragment of the myogenin promoter. Three days after injury, masseter and tibialis anterior (TA) muscles in wild-type mice expressed little or no MRF4 mRNA; whereas these muscles in transgenic mice expressed abundant MRF4 mRNA from both the transgene and the endogenous gene. Thus, MRF4 up-regulation was accelerated in transgenic compared to wild-type regenerating muscles, and expression of the transgene appeared to activate, perhaps indirectly, expression of the endogenous MRF4 gene. At 11 days after injury, regeneration, as measured by cross-sectional area and density of regenerated fibers, was significantly impaired in transgenic TA compared to wild-type TA, whereas at 19 days after injury both transgenic and TA muscle fibers had fully recovered to preinjury values. Regeneration of masseter muscles, which normally regenerate much less completely than TA muscles, was unaffected by the transgene. Thus, the timing of MRF4 up-regulation, as well as additional muscle-specific factors, can determine the progress of muscle regeneration.

Animals↗
PubMed1999

Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer's disease.

We have generated transgenic mice expressing the shortest human tau protein, the microtubule-associated protein that composes paired helical filaments in Alzheimer's disease. Transgenic tau transcripts and proteins were strongly expressed in neurons in the developing and adult brain. In contrast to the endogenous tau that progressively disappeared from neuronal cell bodies during development, the human transgenic tau remained abundant in cell bodies and dendrites of a subset of neurons in the adult. This somatodendritic transgenic tau was immunoreactive with antibodies to tau phosphorylated on Thr181 and Thr231 and with the conformation-dependent Alz50 antibody. A few astrocytes expressing the transgenic tau were strongly immunoreactive with antibodies to additional tau phosphorylation sites, ie, at Ser262/ 356 and Ser396/404. All of these phosphorylation sites have been identified in paired helical filaments-tau proteins. In electron microscopy, the transgenic tau was detected into microtubules in axons and in dendrites but not in cell bodies. Neurofibrillary tangles were not detected in transgenic animals examined up to the age of 19 months. These results indicate that transgenic manipulation of tau expression and intracellular targeting is sufficient per se to affect tau compartmentalization, phosphorylation, and conformation partly as it is observed at the pretangle stage in Alzheimer's disease.

Aging↗
PubMed2002

How to make tetracycline-regulated transgene expression go on and off.

Tetracycline-regulated gene expression systems are widely used to allow temporal and quantitative control of transgene expression in cultured cells and transgenic animals. While working with the Tet-Off system, where tetracycline or the analogue doxycycline suppresses expression, we noted a considerable variability in induced transgene expression after removal of doxycycline. Variable expression of the transgene could not be explained by clonal variation since it was noted when working with clonal cell lines. Instead we found that doxycycline bound nonspecifically to cells and extracellular matrix and was slowly released after it had been removed from tissue culture media. The released doxycycline reached sufficiently high levels to completely suppress transgene expression. The effect was not dependent on cell type or the nature of the transgene. However, robust and rapid transgene expression could be induced if released doxycycline were removed by washing cells 3h after the initial removal of doxycycline. The use of different vector systems, harboring the tetracycline-regulatable components, yielded similar results. These results not only help explain why tetracycline-regulatable transgene expression systems sometimes are variable but also provide simple ways to substantially improve the efficiency, utility, and reliability of these widely used expression systems.

Adenoviridae↗
PubMed2000

A transgenic mouse expressing human CYP1A2 in the pancreas.

A transgenic mouse line expressing the human cytochrome P450 CYP1A2 in the pancreas under the control of the mouse elastase promoter was established. The expression of CYP1A2 was specific to the transgenic pancreas and was not found in the control wild-type mouse pancreas. The level of CYP1A2 expressed in pancreatic microsomes from transgenic mice was comparable to that of the endogenously expressed CYP1A2 protein in the liver, as judged by western blotting analyses. Estrone metabolism was used to determine the activity of CYP1A2 expressed in the pancreas of the transgenic mouse. The transgenic pancreas exhibited almost one-third to one-half of the activity of wild-type or CYP1A2 transgenic mouse liver, whereas the wild-type pancreas demonstrated no activity. The addition of NADPH-cytochrome P450 oxidoreductase to the reaction mixture containing pancreatic microsomes from the transgenic mice did not increase the estrone metabolism activity significantly. This transgenic mouse line provides another useful tool to study human CYP1A2 and its relation to chemical toxicity and carcinogenesis.

Animals↗
PubMed2002

Age-dependent changes in nitric oxide synthase activity and protein expression in striata of mice transgenic for the Huntington's disease mutation.

Huntington's disease (HD) is an autosomal hereditary neurodegenerative disorder caused by an abnormal expansion of the CAG repeats that code for a polyglutamine tract in a novel protein called huntingtin (htt). Both patients and experimental animals exhibit oxidative damage in specific areas of the brain, particularly the striatum. Nitric oxide (NO) is involved in many different physiological processes, and under pathological conditions it may promote oxidative damage through the formation of the highly reactive metabolite peroxynitrite; however, it may also play a role protecting cells from oxidative damage. We previously showed a correlation between the progression of the neurological phenotype and striatal oxidative damage in a line of transgenic mice, R6/1, which expresses a human mutated htt exon 1 with 116 CAG repeats. The purpose of the present work was to explore the participation of NO in the progressive oxidative damage that occurs in the striata of R6/1 mice. We analyzed the role of NO by measuring the activity of nitric oxide synthase (NOS) in the striata of transgenic and control mice at different ages. There was no difference in NOS activity between transgenic and wild-type mice at 11 weeks of age. In contrast, 19-week-old transgenic mice showed a significant increase in NOS activity, compared with same age controls. By 35 weeks of age, there was a decrease in NOS activity in transgenic mice when compared with wild-type controls. NOS protein expression was also determined in 11-, 19- and 35-week-old transgenic mice and wild-type littermates. Our results show increased neuronal NOS expression in 19-week-old transgenic mice, followed by a decreased level in 35-week-old mice, compared with controls, a phenomenon that parallels the changes in NOS enzyme activity. The present results suggest that NO is involved in the process leading to striatal oxidative damage and that it is associated with the onset of the progressive neurological phenotype in mice transgenic for the HD mutation.

Aging↗
PubMed2000

Stromelysin-1 (MMP-3) expression driven by a macrophage-specific promoter results in reduced viability in transgenic mice.

Macrophage expression of matrix degrading metalloproteinases (MMPs) in human atheroma has been found to occur in rupture-prone areas of plaques. To investigate the effect of metalloproteinase activity on plaque stability, we attempted to generate mice that expressed a stromelysin-1 (MMP-3) transgene specifically in macrophages. Promoter sequences taken from a macrophage-tropic lentivirus (visna) were used to drive transgene expression. The transgene construct was expressed in macrophages in vitro and its autoactivation was established by casein zymography. Transgenic mice generated with this construct died at or before birth. No gross anatomical changes were observed in these mice. Embryos arising from a second round of oocyte injections with the transgene were examined at day 16 of gestation. Of the products of conception, approximately 40% resulted in vacant conceptuses. Only one animal of 38 examined carried the transgene and its expression of MMP-3 mRNA at E16 was faintly detected by RT-PCR. When a non-toxic reporter gene, luciferase, was substituted for the MMP-3 cDNA, healthy transgenic mice were produced that expressed the reporter gene in a wide variety of tissue macrophages, including those located in the brain, testis, lung, and thymus. These studies suggest that constitutive expression of MMP-3 in diverse populations of tissue macrophages leads to prenatal or neonatal death in the mouse. It appears likely that more sophisticated transcriptional control of MMP-3 expression will be required in order to generate stromelysin-1 transgenic mice that could be useful models for studying overexpression of this metalloproteinase's activity in the lesional macrophages of atherosclerotic plaques.

Animals↗
PubMed2000

Differential mutation of transgenic and endogenous loci in vivo.

Although chemicals usually induce very similar frequencies of mutations in transgenes and endogenous genes in vivo when given acutely, chronic exposure to N-ethyl-N-nitrosourea (ENU) produced a more complex pattern in which the endogenous locus was spared many mutations. Here, we demonstrate that the effect is neither ENU-specific nor locus-specific, and thus, may be important in the extrapolations of risk assessment and in understanding mutational mechanisms. During chronic mutagen exposure, mutations at the transgene accumulate linearly with time, i.e. in direct proportion to the dose received. In contrast, mutations at the endogenous gene are much less frequent than those of the transgene early in the exposure period and the accumulation is not linear with time, but rather accelerates as the exposure continues. Previous comparisons involved the endogenous Dlb-1 locus and the lacI transgene from the Big BlueMouse in the small intestine. These experiments involved the Dlb-1 locus and the lacZ transgene from the MutaMouse in the small intestine and the hprt locus and the lacZ transgene in splenocytes. Comparisons were made in both tissues after acute and chronic exposures to ENU, the original mutagen, and in the small intestine after exposures to benzo(a)pyrene. All comparisons showed that during chronic exposures mutations at the transgene accumulate linearly with the increasing duration of exposure, whereas induced mutations of the endogenous gene initially accumulate at a slower rate. Thus, the difference in mutational response observed during low chronic treatment is not unique to a particular transgene, endogenous gene, tissue, or mutagen used, but may be a general phenomenon of such genes.

Animals↗
PubMed1996

Age-dependent spatial memory deficits in transgenic mice expressing the human mid-sized neurofilament gene: I.

Previous studies have revealed that the transgenic mouse line expressing the human neurofilament-mid-sized (NF-M) gene evidences age-dependent and cell-specific pathological neurofibrillary accumulation in the central nerve system. In the current study, we investigated the learning and memory processes of NF-M transgenic mice at 3 and 8 months of age in a modified Morris water maze using a series of tasks including those primarily related to reference memory (i.e., spatial learning, reversal learning and probe trials) and to working memory (i.e., matching to sample tasks with or without delays). At 3 months of age, NF-M transgenic mice were indistinguishable from age- and litter-matched non-transgenic wild-type controls on any of the tests of reference and working memory. At 8 months of age, however, the NF-M transgenic mice exhibited significantly poorer performance than the age- and litter-matched wild-type control mice on both reference and working memory tasks. Immunohistological study of the brains of the 8-month-old NF-M transgenic mice revealed spherical and tangle-like neurofilamentous accumulation in their cerebral cortices. These results suggest that NF-M transgenic mice express both age-related histopathological changes and age-dependent learning and memory deficits. Whether NF-M transgenic mice exhibit even more severe behavioral impairments when they become aged is currently under study.

Aging↗
PubMed1999

Promoter activity of mouse kappa opioid receptor gene in transgenic mouse.

The biological activity of mouse kappa opioid receptor (KOR) gene promoter was examined in transgenic mice using a beta-galactosidase (lacZ) reporter strategy for the first time. A lacZ cDNA was inserted at the 5th amino acid in the coding region of a mouse KOR genomic segment containing 3 kb of the 5' regulatory region, to generate a Kor-lacZ fusion gene which was then used to generate transgenic mice. The expression of transgene was demonstrated at the RNA level by reverse transcription-polymerase chain reaction (RT-PCR), and at the protein level by in situ lacZ enzyme assay. From studying three independent transgenic mouse lines that express this transgene, it is concluded that Kor-lacZ expression begins at embryonic day 9.5 (E9.5) and increases in several brain areas and neural tube as embryos develop. At E12.5 and E13.5, Kor-lacZ expression is found primarily in the mantle layer of midbrain, hindbrain and medulla oblongata, cranial ganglion and vagus nerve. At E15.5 and E17.5, the transgene is expressed in eye, ear, neopallial cortex, caudate putamen, lateral ventricle, thalamus, hypothalamus and pons. Therefore, the 3 kb 5' regulatory sequence of the mouse KOR gene is functional in transgenic animals and directs a specific expression pattern recapitulating that of the endogenous KOR gene expression during developmental stages. However, in adult animals, this transgene is only expressed in the brain, indicating that the regulatory information for peripheral expression in the adult is not encoded within this 3 kb upstream sequence.

Age Factors↗
PubMed2003

Pituitary tumorigenesis targeted by the ovine follicle-stimulating hormone beta-subunit gene regulatory region in transgenic mice.

Targeted tumorigenesis in transgenic mice has been a powerful tool for the study of gene expression and oncogenesis, as well as for the production of differentiated immortal cell lines from rare cell types. Follicle-stimulating hormone (FSH) is secreted by the gonadotrope cells of the anterior pituitary gland and plays a pivotal role in mammalian reproduction. Here we have used the regulatory region of the ovine FSH beta gene to direct expression of the SV40 T antigen oncogene to gonadotrope cells in the pituitary of transgenic mice. Two of five transgenic mouse lines bearing this fusion gene rapidly developed pituitary tumors, with appearance of adenomatous foci as early as 6 weeks of age, resulting in death by 12 weeks of age in both genders. Histologic examination of tumor development over time revealed that increases in cell proliferation and dysplasia were accompanied by decreases in synthesis of pituitary hormones, indicating dedifferentiation of the pituitary cells. Histological features observed in these tumors were in agreement with this rapid transformation of cell phenotype. Tumors were multifocal in origin, and the most highly transformed cell types observed consisted of giant pale basophilic cells with enormous hyperploid nuclei associated with infiltrating neuronal-like cells, which were very abundant at later stages of tumor development. Mitotic indices were much higher in transgenic than wild-type pituitaries, as expected. Morphologic analysis of the gonads of these transgenic mice showed no major developmental differences, as compared to wild-type littermates, however the length of the seminiferous tubules in transgenic males was greater than age-matched wild-type animals. Despite this phenotype difference, both genders were fertile, with normal sperm development observed in males and normal estrous cycle stages in females. Moreover, while 8 -- 10-week-old transgenic males had much lower blood levels of FSH than littermates, transgenic female FSH levels were the same as those of wild-type females. These animals offer a unique and potentially useful model of organ-specific tumorigenesis, where a multistage pathway of tumor development is evident, both histologically and temporally. Study of such models will advance our knowledge on the physiological and molecular mechanisms involved in gene expression as well as tumor formation.

Animals↗
PubMed1998

Transgenic mice with cerebral expression of human immunodeficiency virus type-1 coat protein gp120 show divergent changes in short- and long-term potentiation in CA1 hippocampus.

The human immunodeficiency virus type-1 envelope glycoprotein gp120 is shed from the virus and from infected cells and thus can diffuse and interact with a variety of central nervous system cells. Transgenic mice constitutively expressing glial fibrillary acidic protein-driven gp120 from brain astrocytes display neuronal and glial changes resembling abnormalities in human immunodeficiency virus type-1-infected human brains. To assess the neurophysiology of these transgenic mice and determine whether gp120 expression impairs synaptic plasticity, we examined CA1 population excitatory postsynaptic potentials in hippocampal slices from transgenic mice and from non-transgenic controls, using a double-blind protocol. Compared with slices from non-transgenic littermate controls, slices from gp120 transgenic mice showed four significant alterations: (i) increased mean slopes of normalized population excitatory postsynaptic potentials; (ii) larger paired-pulse facilitation after induction of long-term potentiation at 50 ms interpulse intervals; (iii) markedly elevated short-term potentiation after 10 and 20 shocks at 100 Hz; and (iv) a significant reduction in the magnitude of CA1 long-term potentiation. In slices from transgenic mice expressing Escherichia coli beta-galactosidase from the same promoter, paired-pulse facilitation and long-term potentiation were normal. These results indicate that brain slice preparations from gp120 transgenic mice can be used to assess pathophysiological effects of gp120 on neuronal networks. Because short-term potentiation involves presynaptic mechanisms, our results suggest that gp120 expression in these mice enhances either presynaptic glutamate release or postsynaptic glutamate receptor function, or both. These changes could lead to increased Ca2+ influx, thereby contributing to neuronal dysfunction and injury. As long-term potentiation is a cellular model of learning and memory, our results may be relevant to memory (cognitive) impairments seen in patients with AIDS.

Animals↗
PubMed1999

Altered physiology of Purkinje neurons in cerebellar slices from transgenic mice with chronic central nervous system expression of interleukin-6.

The cytokine interleukin-6 is produced at elevated levels within the central nervous system in a number of neurological diseases and has been proposed to contribute to the histopathologic, pathophysiologic, and cognitive deficits associated with such disorders. In order to determine the effects of chronic exposure of interleukin-6 on the physiology of central neurons, we compared the firing properties of cerebellar Purkinje neurons from control mice and transgenic mice that chronically express interleukin-6 within the central nervous system. Extracellular recordings from cerebellar slices revealed that the mean firing rate of spontaneously active Purkinje neurons was significantly reduced in slices from transgenic mice compared to control mice. In addition, a significantly greater proportion of Purkinje neurons from transgenic slices exhibited an oscillatory pattern of spontaneous firing than neurons in control slices. Orthodromic stimulation of climbing fiber afferents evoked similar excitatory synaptic responses (complex spikes) in Purkinje neurons of both transgenic and control mice. However, the inhibitory period following the complex spike (climbing fiber pause) was significantly longer in slices from transgenic mice. Using immunohistochemistry, we also showed that Purkinje neurons express high levels of both the interleukin-6 receptor and its intracellular signaling subunit, gp130, indicating that interleukin-6 could act directly on Purkinje neurons to alter their physiological properties. The interleukin-6 expressing transgenic mice have been shown previously to exhibit a number of histopathological changes in the central nervous system including injury and loss of cerebellar Purkinje neurons. The present data show that these transgenic mice also have altered physiology of cerebellar Purkinje neurons, potentially through a direct activation of interleukin-6 receptors expressed by this neuronal type. Interleukin-6 induced alterations of Purkinje neuron physiology would ultimately affect the flow of information out of the cerebellum, and could thus contribute to the motor deficits observed in the transgenic mice.

Age Factors↗