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At least 307 records · Page 17Linked to original sources
PubMed2004

Stimulation of adenosine A2A receptors elicits zif/268 and NMDA epsilon2 subunit mRNA expression in cortex and striatum of the "weaver" mutant mouse, a genetic model of nigrostriatal dopamine deficiency.

Interaction between basal ganglia and cerebral cortex is critical for normal goal-directed behavior. In the present study we have used the immediate early gene zif/268, as functional marker to investigate how the stimulation of adenosine A2A receptors, i.e. of the "indirect" striatal output pathway, affects striatal and cortical function in "weaver" mouse, a genetic model of dopamine deficiency. Furthermore, we have examined the effect of A2A receptor stimulation on glutamate receptor expression in the "weaver" brain. A single injection of CGS21680 (A2A receptor agonist), induced strong expression of zif/268 mRNA, detected by in situ hybridization, not only in striatum but also in the motor cortex of the "weaver" mutant. This cortical response seems to be elicited through the basal-ganglia-thalamo-cortical circuit, rather than through a direct cortical effect, since A2A receptors are not detectable in cortex according to our autoradiographic study. Co-administration of CGS21680 and quinpirole (D2 receptor agonist) attenuated the expression of zif/268 mRNA in dorsal striatum but not in motor cortex, indicating that the cortical response is dopamine-D2-receptor-independent. However, this co-administration induced an increase in zif/268 mRNA expression in somatosensory cortex, which could rely on disinhibition of the thalamo-cortical pathway. The motor cortical response could be of clinical interest, as it would further stimulate the "indirect" striatal pathway in a feed forward circuit, thus worsening the parkinsonian symptoms. Furthermore, the up-regulation of epsilon2 subunit mRNA of the NMDA receptor, induced by CGS21680 administration, seen in striatum and cortex of the "weaver" mouse, would lead to overactivity of these receptors worsening dyskinesias. These results suggest adenosine to play a significant role in regulating striatal and cortical neurochemistry in a dopamine-depleted mouse. Blockade of these receptors by specific A2A antagonists could ameliorate parkinsonian symptoms.

Adenosine↗
PubMed2006

Synaptic hyperexcitability of deep layer neocortical cells in a genetic model of absence seizures.

We used sharp-electrode, intracellular recordings in an in vitro brain slice preparation to study the excitability of neocortical neurons located in the deep layers (>900 microm from the pia) of epileptic (180-210-days old) Wistar Albino Glaxo/Rijswijk (WAG/Rij) and age-matched, non-epileptic control (NEC) rats. Wistar Albino Glaxo/Rijswijk rats represent a genetic model of absence seizures associated with generalized spike and wave (SW) discharges in vivo. When filled with neurobiotin, these neurons had a typical pyramidal shape with extensive apical and basal dendritic trees; moreover, WAG/Rij and NEC cells had similar fundamental electrophysiological and repetitive firing properties. Sequences of excitatory postsynaptic potentials (EPSPs) and hyperpolarizing inhibitory postsynaptic potentials (IPSPs) were induced in both the strains by electrical stimuli delivered to the underlying white matter or within the neocortex; however, in 24 of 55 regularly firing WAG/Rij cells but only in 2 of 25 NEC neurons, we identified a late EPSP that (1) led to action potential discharge and (2) was abolished by the N-methyl-D-aspartate (NMDA) receptor antagonist 3,3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonate (20 microM; n = 8/8 WAG/Rij cells). Finally, we found that the fast and slow components of the stimulus-induced IPSPs recorded during the application of glutamatergic receptor antagonists had similar reversal potentials in the two strains, while the peak conductance of the fast IPSP was significantly reduced in WAG/Rij cells. These findings document an increase in synaptic excitability that is mediated by NMDA receptors, in epileptic WAG/Rij rat neurons located in neocortical deep layers. We propose that this mechanism may be instrumental for initiating and maintaining generalized SW discharges in vivo.

Animals↗
PubMed1991

[Various genetic models in Crohn disease].

Crohn's disease has a genetic predisposition. In the light of epidemiological data, especially the type of familial clustering, simple modes of inheritance can be excluded. At the first glance, our results implied a polygenic multifactorial basis. Further processing of our data by the "mixed model" of Morton revealed a higher probability for a recessive gene with low penetrance. However, the differences in fit between the various models are relatively slight. Also considering ascertainment problems, a definite decision concerning an appropriate model must be deferred until sure genetic markers have been identified. Nevertheless, only a certain number of manifestations may be ascribed to a genetic predisposition, others have to be catagorized as phenocopies.

Adolescent↗
PubMed2002

Suppression of absence seizures by electrical and pharmacological activation of the caudal superior colliculus in a genetic model of absence epilepsy in the rat.

Activation of the superior colliculus has been shown to reproduce the antiepileptic effect of the inhibition of the substantia nigra reticulata. A circuit involving neurons of the caudal deep layers of the superior colliculus has been suggested to control brain stem convulsive seizures. The present study was designed to examine whether a similar circuit is also involved in the control of absence seizures. For this, activation of either the rostral or caudal parts of the deep and intermediate layers of the superior colliculus was applied in a genetic model of absence seizures in the rat (GAERS). Single-shock (5 s) electrical stimulation of the rostral and caudal superior colliculus interrupted ongoing spike-and-wave discharges at an intensity (antiepileptic threshold) significantly lower than the intensity inducing behavioral effects. At this intensity, no interruption of licking behavior was observed in water-deprived rats. Repeated stimulations (5 s on/5 s off) at the antiepileptic threshold reduced absence seizures only during the first 10 min. Bilateral microinjection of a GABA antagonist (picrotoxin, 33 pmol/side) significantly suppressed spike-and-wave discharges when applied in the caudal aspect of the superior colliculus. This antiepileptic effect appears dissociated from an anxiogenic effect, as tested in an elevated plus maze test. Finally, bilateral injection of picrotoxin (33 pmol/side) appeared more effective in the superficial and intermediate layers of the caudal superior colliculus, whereas such injections had only weak effects on absence seizures when applied in the deep layers. These results suggest that a specific population of neurons located in the intermediate and superficial layers of the caudal superior colliculus is involved in the inhibitory control of absence seizures. It may constitute an important relay for the control of absence seizures by the basal ganglia via the substantia nigra reticulata.

Animals↗
PubMed2002

Cardiac adenosine production in rat genetic models of low and high exercise capacity.

We previously demonstrated that Copenhagen (COP) and DA inbred rat strains show a wide difference in a test for aerobic treadmill running that correlated positively with isolated cardiac function. The purpose of this study was to test adenosine production as a candidate intermediate phenotype that may explain part of the difference in running and cardiac performance in these genetic models for low and high aerobic capacity. Adenosine production was measured as the activity of soluble 5'-nucleotidase and membrane-bound ecto-5'-nucleotidase in the membrane pellet and supernatant fractions of left and right ventricular muscle and gracilis muscle taken from 10 DA and 10 COP rats. Ecto-5'-nucleotidase activity in the membrane pellet of hearts from both DA and COP accounted for the vast majority of the total tissue adenosine production (>90% in the left ventricle and >80% in the right ventricle). Ecto-5'-nucleotidase activity in the pellet fraction was significantly higher in the left (22.4%) and right (46.1%) ventricles of DA rats compared with COP rats, with no differences in total protein content. There were no significant differences between the strains for 5'-nucleotidase activity in the cardiac supernatant, the gracilis pellet, or the gracilis supernatant. These data support the hypothesis that an increase in cardiac adenosine production may contribute to the greater aerobic running capacity of the DA rats.

5'-Nucleotidase↗
PubMedDate not supplied

Effects of long-term treatment with alpha-glucosidase inhibitor on the peripheral nerve function and structure in Goto-Kakizaki rats: a genetic model for type 2 diabetes.

BACKGROUND: Continuous hyperglycemia is implicated in the pathogenesis of chronic diabetic complications. It is not well known, however, how and to what extent the development of neuropathy is inhibited by blood glucose control in subjects with Type 2 diabetes. We investigated therefore the effects of an alpha-glucosidase inhibitor (voglibose; Vg) on neuropathic changes in diabetic Goto-Kakizaki (GK) rats, a genetic model for Type 2 diabetes. METHODS: Twelve week-old male GK rats were given a diet containing Vg (50 ppm) for 24 weeks and monitored for blood glucose, glycated hemoglobin, motor nerve conduction velocity (MNCV). At the end of the administration period (Na(+), K(+))-ATPase activity and the structure of the peripheral nerves were examined. Age- and sex-matched normal Wistar rats were treated similarly and served as controls. RESULTS: GK rats showed fasting hyperglycemia after 8 weeks of age, and Vg treatment significantly lowered levels of blood glucose and glycated hemoglobin. Slowing of MNCV to 80% of normal control levels was detected in GK rats. Vg treatment inhibited this delay by 24% at 24 weeks and 57% at 36 weeks of age. Nerve (Na(+), K(+))-ATPase activity was reduced to 80% of normal control levels in GK rats and was restored by Vg treatment. Teased fiber studies revealed a higher incidence of fibers with paranodal, segmental demyelination and axonal degeneration in GK rats. Vg treatment significantly inhibited the development of these nerve-fiber abnormalities. CONCLUSIONS: Lowering of high blood glucose levels achieved by the use of Vg in GK rats improved MNCV and demyelinative nerve changes with restoration of (Na(+), K(+))-ATPase activity.

Animals↗
PubMed1983

Genetic models for the study of aggressive behavior.

The analysis of genetic contributions to aggressive behavior is both conceptually and methodologically difficult, so that substantive findings remain sparse. Like other major psychiatric disease states, inappropriately aggressive behavior must be considered a multifactorial disorder, with both genetic and environmental contributions required for clinical expression. The documented heterogeneity of these determinants suggests the futility of searching for unitary causes. This contribution reviews studies of major gene effects in inbred strains of mice with high aggressivity, and considers the relevance of some rare single-gene disorders in man which include uncontrollably aggressive behavior as part of the phenotype.

Aggression↗
PubMed2004

On the activity of the corticostriatal networks during spike-and-wave discharges in a genetic model of absence epilepsy.

Absence seizures are characterized by impairment of consciousness associated with widespread bilaterally synchronous spike-and-wave discharges (SWDs) in the electroencephalogram (EEG), which reflect highly synchronized oscillations in thalamocortical networks. Although recent pharmacological studies suggest that the basal ganglia could provide a remote control system for absence seizures, the mechanisms of propagation of epileptic discharges in these subcortical nuclei remain unknown. In the present study, we provide the first description of the electrical events in the corticostriatal pathway during spontaneous SWDs in the genetic absence epilepsy rats from Strasbourg (GAERS), a genetic model of absence epilepsy. In corticostriatal neurons, the SWDs were associated with suprathreshold rhythmic depolarizations in-phase with local EEG spikes. Consistent with this synchronized firing in their excitatory cortical afferents, striatal output neurons (SONs) exhibited, during SWDs, large-amplitude rhythmic synaptic depolarizations. However, SONs did not discharge during SWDs. Instead, the rhythmic synaptic excitation of SONs was shunted by a Cl(-)-dependent increase in membrane conductance that was temporally correlated with bursts of action potentials in striatal GABAergic interneurons. The reduced SON excitability accompanying absence seizures may participate in the control of SWDs by affecting the flow of cortical information within the basal ganglia circuits.

Action Potentials↗
PubMed2000

Postnatal growth in a mouse genetic model of classical phenylketonuria.

Because of the ethical problems of withholding dietary treatment from patients with phenylketonuria, effectively studying long-term effects such as postnatal growth rates is difficult or impossible. The only literature available on the growth rate of phenylketonurics dates from the era before effective dietary treatment regimens were instituted routinely. Although some of these studies suggest that these patients have a reduced growth rate, whether this is a consistent feature of the untreated phenylketonuric is unclear. The mutant mouse line BTBR-Pahenu, a genetic model for human phenylketonuria, provides an opportunity to conduct studies that will clarify this issue. In this study, the weights of newborn mice were monitored from about 7 to 40 days after birth. Comparison to heterozygous, sex-matched littermates revealed a reduction in the size of homozygous mutants throughout the study. Therefore, reduced postnatal growth is an abiding feature of phenylketonuria in this mouse model. This finding not only helps to document the association between size reduction and untreated phenylketonuria but also sets the stage for studies designed to investigate the means by which size reduction occurs.

Animals↗
PubMed1997

[A new wave of behavior genetic modeling using covariance structure analysis].

A number of useful methods for analyzing covariance structure have been proposed in the studies of human behavior genetics, reflecting the fact that the behavior genetic studies are one of the main origins of covariance structure model. In this paper, I review recent progress on methodology for behavior genetic studies of twins and families from the standpoint of the structural equation modeling. Especially, genetic ACE (additive genetic, common environment and random environment) model, multivariate ACE model, genetic factor analysis model and twin-parent model are focused upon. This review also discusses how to construct applied structural equation models which are useful for psychological research.

Factor Analysis, Statistical↗
PubMedDate not supplied

ErbB4 signaling during breast and neural development: novel genetic models reveal unique ErbB4 activities.

The erbB4 gene encodes one of the four members of the mammalian ErbB family of transmembrane tyrosine kinases. The ErbB4 protein plays a role as a receptor for the neuregulins, a large group of structurally related molecules and a few other epidermal growth factor (EGF)-related polypeptides, such as heparin-binding EGF, betacellulin and epiregulin. The importance of this receptor tyrosine kinase in development has been demonstrated by the generation of mice with a targeted inactivation of the erbB4 gene. Such mice die by embryonic day eleven due to defective trabeculation in the heart, precluding analysis of phenotypes at later stages in development and in the adult. Now, using two unique genetic approaches our laboratories succeeded in overcoming this obstacle. In the first approach, the heart defects of ErbB4 null mutant mice were rescued by transgenic expression of an ErbB4 cDNA under a cardiac-specific myosin promoter. This allowed the generation of ErbB4 mutants that develop into adulthood and are fertile. In the second approach, the role of ErbB4 during mammary gland development was specifically addressed by Cre-mediated deletion of both erbB4 alleles within the mammary epithelium. Below we discuss the progress made studying these genetic models in understanding the physiological roles of ErbB4 with a focus on the mammary gland and the nervous system.

Animals↗
PubMedDate not supplied

Protective effects of TRH and its analogues in chemical and genetic models of seizures.

TRH shows strong influence on neuronal excitability and may participate in the regulation of seizures. We investigated the effect of TRH and its stable analogues on seizures induced by intravenous (i.v.) infusion of pentetrazole in rats. The data showed that i.v. administration of TRH (10 and 20 mg/kg), RGH-2202 (0.1 mg/kg) and Z-p-Glu-His-Pro-NH2 (10 mg/kg) increased threshold for pentetrazole-induced clonic seizures, but did not affect the tonic ones. Another stable analogue of TRH, 1p-Glu-Tyr-Pro-NH2 (0.1-10 mg/kg), had no effect on pentetrazole-induced seizures. In further study, effects of TRH and RGH-2202 were examined in WAG/Rij rats, a genetic model of absence epilepsy. TRH (25 and 50 micrograms i.c.v.) decreased dose-dependently the number and mean duration of spike-wave discharges in cortical EEG of WAG/Rij rats at 90 and 120 min after the peptide administration. On the other hand, RGH-2202 (1 microgram i.c.v.) significantly decreased only the number of spike-wave discharges at 60 min post-injection. These results confirm that TRH and some of its analogues have moderate antiepileptic activity.

Action Potentials↗
PubMed1981

Genetic models of sex effect in unipolar affective illness.

Family study data on unipolar affective illness are analyzed by multiple threshold models of inheritance that incorporate sex effect. In these models males and females share a common genetic-environmental liability, but the less prevalent sex, i.e., males, has a higher genetic threshold for the disorder. Neither single major locus (SML) nor multifactorial-polygenic (MFP) transmission can account for the sex differences in the morbid risk for unipolar disorder. The implications for genetic research in affective disorders are discussed.

Chromosome Mapping↗
PubMed1991

Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis.

We have generated transgenic mouse lines carrying and expressing wild-type and 3'-modified human tumour necrosis factor (hTNF-alpha, cachectin) transgenes. We show that correct, endotoxin-responsive and macrophage-specific hTNF gene expression can be established in transgenic mice and we present evidence that the 3'-region of the hTNF gene may be involved in macrophage-specific transcription. Transgenic mice carrying 3'-modified hTNF transgenes shows deregulated patterns of expression and interestingly develop chronic inflammatory polyarthritis. Treatment of these arthritic mice with a monoclonal antibody against human TNF completely prevents development of this disease. Our results indicate a direct involvement of TNF in the pathogenesis of arthritis. Transgenic mice which predictably develop arthritis represent a novel genetic model by which the pathogenesis and treatment of this disease in humans may be further investigated.

Animals↗
PubMed2003

Zebra fish: an uncharted behavior genetic model.

The zebra fish has been a preferred subject of genetic analysis. It produces a large number of offspring that can be kept in small aquaria, it can be easily mutagenized using chemical mutagens (e.g., ethyl nitrosourea [ENU]), and high-resolution genetic maps exist that aid identification of novel genes. Libraries containing large numbers of mutant fish have been generated, and the genetic mechanisms of the development of zebra fish, whose embryo is transparent, have been extensively studied. Given the extensive homology of its genome with that of other vertebrate species including our own and given the available genetic tools, zebra fish has become a popular model organism. Despite this popularity, however, surprisingly little is known about its behavior. It is argued that behavioral analysis is a powerful tool with which the function of the brain may be studied, and the zebra fish will represent an excellent subject of such analysis. The present paper is a proof of concept study that uses pharmacological manipulation (exposure to alcohol) to show that the zebra fish is amenable to the behavioral genetic analysis of aggression and thus may allow us to reveal molecular mechanisms of this behavioral phenomenon relevant to vertebrates.

Aggression↗
PubMed2002

Myocardial function in rat genetic models of low and high aerobic running capacity.

We recently evaluated treadmill aerobic running capacity in 11 inbred strains of rats and found that isolated working left ventricular function correlated (r = 0.86) with aerobic running capacity. Among these 11 strains the Buffalo (BUF) hearts produced the lowest and the DA hearts the highest isolated cardiac output. The goal of this study was to investigate the components of cardiac function (i.e., coronary flow, heart rates, stroke volume, contractile dynamics, and cross-bridge cycling) to characterize further the BUF and DA inbred strains as potential models of contrasting myocardial performance. Cardiac performance was assessed using the Langendorff-Neely working heart preparation. Isolated DA hearts were superior (P < 0.05) to the BUF hearts for cardiac output (63%), stroke volume (60%), aortic +dP/dt (47%), and aortic -dP/dt (46%). The mean alpha/beta-myosin heavy chain (MHC) isoform ratio for DA hearts was 21-fold higher relative to BUF hearts. At the steady-state mRNA level, DA hearts had a fivefold higher alpha/beta-ratio than the BUF hearts. The mean rate of ATP hydrolysis by MHCs was 64% greater in DA compared with BUF ventricles. These data demonstrate that the BUF and DA strains can serve as genetic models of contrasting low and high cardiac function.

Adenosine Triphosphate↗
PubMed2000

[Model genetic system for analysis of attachment of HeT-A elements to terminal deletions in Drosophila melanogaster].

Telomeres of Drosophila consist of multiple copies of LINE-like transposable elements. These elements are assigned to two classes, HeT-A and TART. They are attached to terminal deletions at their 3' end, thus compensating for the absence of telomerase in Drosophila cells. The attachment of HeT-A elements to the X-chromosome terminal deletions of the regulatory region of the yellow gene was studied. It was shown that, in the case of degradation of the yellow promoter sequence (chromosome underreplication), the Het-A promoter located at the 3' end of this element can activate transcription of the gene. The minimal size of the 3'-end HeT-A element sequence sufficient for the yellow expression was shown to be 400 bp. Since the yellow mutation is expressed phenotypically and the gene impairment is not lethal, we created a convenient model genetic system based on this effect. Using this system, the frequency of attachments of the HeT-A elements to the chromosome end can be visually recorded. This frequency varied in a wide range (from 0.2 x 10(-4) to 2 x 10(-3)) and was strain-specific.

Animals↗