[In vitro study of fatty acids synthesized in brain microsomes of normal and quaking mice].
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[Study of cerebral lipids in "quaking" mice during myelinization].
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Age Factors↗
[Biosynthesis of fatty acids in brain microsomes of normal and quaking mice].
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Animals↗
Developmental expression of glial fibrillary acidic protein and actin-encoding messages in quaking and control mice.
Quaking is a neurological mutation leading to pleiotropic phenotypic expression, the most prominent being disturbed myelin formation in the central nervous system (CNS) with minor abnormalities in the peripheral nervous system. Previous immunochemical measurements of glial fibrillary acidic protein (GFAP) revealed a marked increase in the protein in several areas of the CNS. To further characterize the regulation parameters of GFAP synthesis, we analyzed the levels of GFAP mRNA in 5 regions of the CNS, some with elevated levels of GFAP and some without. This was compared to the developmental expression of GFAP transcripts in the same regions in normal mice. To establish the specificity of the variations observed with this astroglial specific message, we conducted a similar investigation with actin RNA which is expressed by several cell types in the CNS. Both the actin and the GFAP message were found to be increased in the adult mutant throughout the CNS. In 2-year-old normal mice the messengers for both cytoskeleton proteins were expressed in a higher amount than in young adults.
Actins↗
Phenytoin antagonism of electrically induced maximal seizures in frogs and mice and effects on central nervous system levels of adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate.
Phenytoin antagonized the electroshock-induced increase in levels of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) in cerebrum and cerebellum, respectively, from CF-1 mice. However, the effective dose range of phenytoin for significant reduction of the elevated levels of cAMP and cGMP was 2 to 5 times higher than that for prevention of tonic hindlimb extension in 95% of mice. The effective dose range of phenytoin for alteration of cyclic nucleotide levels was nearer to that for preventing tonic flexion and clonus; endpoints which are less relevant to anticonvulsant efficacy than is prevention of tonic hindlimb extension. Also , the greatest reduction in cyclic nucleotide levels occurred at a dose (100 mg/kg) which produced toxic signs in mice. Quaking mice (qk/qk), a mutant strain which exhibits spontaneous seizures, did not have abnormal levels of cAMP or cGMP in cerebrum or cerebellum, and a dose of phenytoin (15 mg/kg) which abolished all seizure activity did not alter levels of these cyclic nucleotides. In frogs, the electroshock-associated increase in levels of cAMP in the central nervous system was not altered by phenytoin even when the doses administered were up to twice the ED95 for prevention of tonic hindlimb extension. Because these data from mice and frogs show that the anticonvulsant effect of phenytoin is dissociated, by dose, from effects on central nervous system cyclic nucleotide levels, it is doubtful that the alteration of cyclic nucleotide levels is a mechanism by which phenytoin exerts its anticonvulsant effect
Animals↗
Endogenous cerebellar soluble lectin and its ligands in central nervous system myelin of quaking and jimpy mutant mice.
The presence of an endogenous 'cerebellar soluble lectin' (CSL) involved in myelin compaction and myelination was analyzed in the dysmyelinating mutant mice quaking and jimpy. The primary defect in these mutations with severe hypomyelination is still unknown in the quaking mutant but results from a single mutation in the proteolipid protein gene in the jimpy mutant. Both immunocytochemical and immunoblotting techniques showed that CSL was not considerably reduced in its expression in the myelin fraction purified from adult quaking mutants. Furthermore, the myelin-associated glycoprotein and an axonal glycoprotein with a relative molecular weight (Mr) of 31 kilodaltons (kDa) were not decreased in quaking mice. This contrasted with several glycoproteins of Mr 23, 18, 16 and 12 kDa which were absent from the purified quaking myelin. In myelin preparations obtained from the jimpy mutant the CSL level was considerably reduced. This defect did not result from a deficient synthesis of CSL. However, as in the quaking mutation low-Mr glycoproteins were lacking. The nature of the low-Mr glycoproteins absent in quaking and jimpy mice is discussed in relation to previous reports on myelin glycoproteins. In the various mutants, due to different primary mutations, a similar absence of myelin compaction was observed, which could be associated with a deficient level of low-Mr glycoproteins. It is thus postulated that these molecules are essential for ensuring myelin compaction as ligands for the endogenous CSL.
Animals↗
Biochemical and immunohistochemical studies on dysmyelination of quaking mutant mice in vivo and in vitro.
Dysmyelination in the central nervous system of the quaking mutant mouse was studied biochemically and immunohistochemically. We found, by measuring CNPase activity, that myelination in the central nervous system of quaking mice was affected to a different degree in different areas. The pallium cerebri was the most severely affected and the medulla and spinal cord were least affected. The density of astroglia observed by GFA staining wash higher in the white matter of quaking mice than in controls, but the total area of the white matter in the cerebellum was smaller in the quaking mice than in the controls. The DNA content in the pallium cerebri and brain stem showed no increase and that of the cerebellum was even lower in quaking mice than in the controls. Hypertrophy of the astroglia was observed in the white matter of the cerebellum of quaking mice, though Bergmann astroglial fibers in the molecular layer did not show any hypertrophy. The cerebella of quaking mice in primary culture showed very poor myelination under the phase-contrast microscope. However, Purkinje cells from the quaking mutants appeared normal with regard to Bodian silver impregnation, hematoxylineosin staining, and Purkinje cell specific P 400 protein. Addition of the conditioned culture medium of qk/qk to the culture of the control cerebellum did not interfere with the myelination. We concluded that the cause of dysmyelination in the quaking mouse could be a genetic defect of the oligodendroglia rather than hypertrophy of the astroglial cells.
2',3'-Cyclic-Nucleotide Phosphodiesterases↗
Abnormal postnatal ontogeny of the locus coeruleus in the epileptic mutant mouse quaking.
The tonic-clonic convulsions of the quaking mutant mice have been shown to be associated with the hyperplasia of the nucleus locus coeruleus, the origin of most brain noradrenergic neurons. In the present study, the postnatal ontogeny of the locus coeruleus has been studied by tyrosine hydroxylase immunolabeling in the mutant mice quaking and their controls at postnatal days 1, 30 and 90. In the control mice, the number of immunoreactive neuronal cell bodies increased significantly in the rostral half of the locus coeruleus between birth and postnatal day 30, while it decreased significantly in the caudal half between birth and adulthood. Thus, during postnatal maturation, the distribution of locus coeruleus neurons was shifted in the rostral direction. In the quaking mutant mice, while the increase of immunolabeling between birth and postnatal day 30 was observed in the rostral half of the locus coeruleus, no diminution could be found in the caudal half between birth and adulthood. As a result, the rostral shift of tyrosine hydroxylase immunoreactivity was not observed. Consequently, in adult mice, the caudal part of the mutants locus coeruleus appeared to contain significantly more neurons than the corresponding region in the controls. These results indicate that the hyperplasia of the locus coeruleus of the quaking mice that we had previously reported results from an alteration of the postnatal maturation of this nucleus. This developmental abnormality might be a primary determinant of the inherited epilepsy of the quaking mutant mice.
Aging↗
Ultrastructural observation on the thalamic neuronal inclusions in young mice.
Neuronal intracytoplasmic inclusions were found in the ventrolateral and posterior nuclei of the thalamus of 3-month-old thiamine-deficient mice and quaking mice. An electron-microscopic study revealed that these inclusions were composed of condensation of parallel rectilinear 10-nm filaments with interconnecting cross-bridges as a hallmark of neurofilaments. They were morphologically indistinguishable from those described in aged mice. This observation indicates that neuronal inclusions in the thalamus, which have been constantly reported in aging mice, can be seen even in young mice in the presence of cellular metabolic disturbances.
Animals↗
Reproductive and neurological Quaking(viable) phenotypes in a severe combined immune deficient mouse background.
The quaking(viable) (qkv) mutation, a spontaneous deletion of a multigenic region encompassing roughly 1 Mb at 5.9 cM on the proximal end of mouse chromosome 17, causes severe trembling in all homozygous animals and infertility in all homozygous males. Physiologically, quaking mice exhibit dysmyelination and postmeiotic spermatogenic arrest. Molecular defects in Qkv mice occur in the affected tissues, indicating the primary causes of these pathologies are cell autonomous. However, because both the reproductive and neurological defects are in immune-privileged sites and because some similar pathologies at both sites have been shown to be immune mediated, we tested whether the immune system participates secondarily in manifestation of Qkv phenotypes. The qkv mutation was bred into a severe combined immune-deficient mouse line (SCID; devoid of mature B and T cells) and penetrance of the neurological and the male sterile phenotypes was measured. Results showed that neither defect was ameliorated in the immune-deficient background. We conclude that the Qkv pathologies do not likely involve a B- or T-cell-dependent response against these immune-privileged sites.
Animals↗
Alterations in the accumulation patterns of polyamines in brains of myelin-deficient mice.
Quaking mutants and jimpy mutants of mice have known deficiencies of myelination of the central nervous system, as well as lesser involvement of the peripheral nervous system. Both mutants also have altered polyamine synthesis and accumulation, particularly in the hindbrain and spinal column. The ratio of spermidine/spermine, which generally is higher in tissues with high rates of biosynthetic activity, was significantly lower in the mutants as compared to their normal siblings. In quaking mutants, 5 months of age, the spermidine concentration of hindbrain and spinal column was 60% that of controls. In contrast, the decreased spermidine/spermine ratio in jimpy mutants resulted from a marked increase in the spermine concentration in both forebrain and hindbrain. Alterations in the spermidine/spermine ratio could lead to reductions in the biosynthetic potential of the brain during development.
Adenosylmethionine Decarboxylase↗
Distribution of [3H]clonidine binding sites in the brain of the convulsive mutant quaking mouse: a radioautographic analysis.
The radioautographic analysis of [3H]clonidine binding was performed on brain slices from the convulsive mutant mice quaking and their controls of the same strain. In the quaking mice significant increases were observed mostly in the brainstem and the cerebellum, but also in a few regions of the forebrain, such as the lateral and medial thalamic nuclei, the medial geniculate nucleus, the amygdala and the hypothalamus. Other regions, such as the cerebral cortex and the hippocampus, which are classically involved in various models of epilepsy, but not in the quaking mice, did not show any modification of [3H]clonidine binding. A high degree of correlation was found between the structures with an increased density of alpha 2-adrenoceptor binding sites and the distribution of regions from which seizures can be elicited by intracerebral electrical stimulation in head-restrained quaking mice. This comparison emphasizes the role of noradrenaline acting at the level of alpha 2-adrenoceptors in the epileptic syndrome of the quaking mutants.
Animals↗
It's a double knock-out! The quaking mouse is a spontaneous deletion of parkin and parkin co-regulated gene (PACRG).
Mutations in the parkin gene (PRKN) are the commonest cause of juvenile and early-onset parkinsonism. However, the pathogenic mechanism by which loss of parkin protein results in degeneration of dopaminergic neurons remains elusive. Animal models provide a useful tool for the study of development and disease, and the recent production of transgenic fly and mouse parkin deficient models allows investigation of the molecular role of parkin in dopamine regulation and nigrostriatal function. We have identified the mouse mutant Quaking as a spontaneously occurring PRKN knockout. The quaking mutation is a deletion of approximately 1.17 Mb of mouse chromosome 17, resulting in the deletion of the entire promoter and first five coding exons of PRKN In addition, the recently described Parkin Co-Regulated Gene (PACRG) is completely deleted. Homozygous Quaking mice show a complete loss of PRKN and PACRG mRNA and protein. These mice will constitute a useful additional model for studies of the molecular role of parkin and PACRG in neurodegeneration.
Animals↗
Effects of drugs affecting the noradrenergic system on convulsions in the quaking mouse.
Handling-induced convulsions in the quaking mouse can be blocked by: phenobarbital, pentobarbital or phenytoin; postsynaptic alpha-adrenoceptor agonists (noradrenaline, phenylephrine, CRL 40028); presynaptic alpha-adrenoceptor blockers (yohimbine, mianserine); catecholamine liberating agent (amphetamine); noradrenaline reuptake inhibitors (cocaine, imipramine, desipramine). Moreover, the protective effect of yohimbine was antagonized by clonidine, prazosin or alpha-methylparatyrosine, and the protective effect of CRL 40028 was antagonized by prazosin but not by alpha-methyltyrosine. Drugs acting by other mechanisms (pilocarpine, atropine, trihexyphenidyl, (--)-5-HTP, methysergide, pimozide, clonidine, alpha-methyl DOPA, prazosin, isoprenaline, salbutamol) did not protect against convulsions. A slight protection was obtained with high doses of apomorphine and also with (+/-)-propranolol. This effect is probably not related to blockade of beta-adrenoceptors because the same effect was obtained with (+)propranolol. In young quaking mice, where susceptibility to convulsions is low, both postsynaptic alpha-adrenoceptor blockers and presynaptic alpha-adrenoceptor antagonist lowered the convulsive threshold. Thus, this seems to constitute an interesting model for the in vivo study of substances which affect the central alpha-adrenoceptors either pre- or postsynaptically.
Animals↗
Supernumerary locus coeruleus neurons as a determinant of inherited epilepsy in the convulsive mutant mouse quaking.
In quaking mice (a genetic model of epilepsy with an increased number of noradrenergic neurons) bilateral electrolytic coagulation of locus coeruleus (LC) in adult mice inhibited the convulsions elicited by somatic stimulations while neonatal 6-hydroxydopamine (6-OHDA) treatment remained ineffective upon the convulsions. Biochemical effects of the two treatments differed only in the brainstem where electrolytic lesion decreased while 6-OHDA treatment increased noradrenaline (NA) and 3-methoxy 4-hydroxyphenylethyleneglycol (MHPG) levels. Our results suggest that supernumerary LC neurons mediate the convulsions of the mutants through an action presumably restricted to the brainstem.
Animals↗
Seizures can be triggered by stimulating non-cortical structures in the quaking mutant mouse.
Mutant Quaking mice (C57BL/6J) display convulsive tonic-clonic seizures that can be either spontaneous or triggered by manipulation of the animal or by auditory stimulation. Several abnormalities have been found (especially in the noradrenergic system) in the brainstem of this mutant strain. We first verified by electrophysiological recording that the cerebral cortex was not involved in the generation or in the development of these fits. Then we showed that tonic-clonic seizures similar to those obtained in the freely moving animal were triggered by low-threshold (LT, 5-50 microA) or high-threshold (HT, 55-150 microA) stimuli performed during head restraint. LT stimuli were mostly efficient in a number of ponto-bulbar and mesencephalic structures, including several reticular nuclei, the locus coeruleus, the nucleus subcoeruleus and the red nucleus, whereas HT stimuli were generally necessary to trigger fits by stimulating the nuclei pontis, the substantia nigra, the central gray area and the cerebellar nuclei. Seizures were also provoked at the diencephalic level with LT stimulation delivered in the medial thalamic area, the nucleus reticularis thalami and some subthalamic regions (zona incerta, H field of Forel). In contrast, no fits were obtained by stimulating the cerebellar cortex and the inferior colliculus, the ventral and lateral groups of thalamic nuclei or the telencephalic regions (hippocampus, amygdala, caudate nucleus, putamen and cerebral cortex), with the exception of the globus pallidus.
Acoustic Stimulation↗
Anesthetic requirement in the quaking mouse.
Anesthetic requirements for nitrous oxide, cyclopropane, enflurane, and isoflurane were determined in quaking mice (autosomal recessive mutants with a deficiency in central nervous system myelin) and their littermate (non-quaking) controls. Although quaking mice had significantly (15 to 23 per cent) lower nitrous oxide and cyclopropane rolling-response ED50S than did littermate controls, enflurane and isoflurane rolling-response ED50S were not significantly different. Tail-clamp ED50S for cyclopropane, enflurane, and isoflurane in quaking and control mice were not significantly different. Myelin from quaking mice showed higher levels of palmitic, stearic, and docosahexaenoic acids, lower levels of oleic, eicosenoic, and docosatetraenoic (and/or nervonic) acids, and a lower cholesterol/phospholipid ratio. In contrast, the phospholipid, fatty acid, and cholesterol compositions of synaptic plasma membranes isolated from quaking and control mice were essentially identical. It is concluded that gross alterations in the lipid composition of central nervous system myelin have little or no influence on anesthetic requirement.
Anesthetics↗
[Characteristics of the brain dopamine system in mice carrying the quaking neurological mutation].
Dopamine (DA) metabolism and the response to dopaminergic drugs were studied in quaking (QK) mice with neurological mutation expressed in demyelinization of the brain neurons and constant shaking. It has been shown that apomorphine in a low dose (0.25 mg/kg) produced a more significant decrease in locomotor activity in Qk than in control mice. Qk mice appeared to be less sensitive to the blockade by haloperidol of apomorphine (2.5 mg/kg)-induced climbing. DA1 receptor agonist, SKF-38393 caused less pronounced climbing in Qk mice than in the control. There were no changes in DA level in striatum and n. accumbens, whereas 3,4-dihydroxyphenylacetic acid in n. accumbens and homovanillic acid level in striatum were elevated. It was suggested that the increased DA metabolism and the altered sensitivity of pre- and postsynaptic DA receptors are involved in the shaking behaviour of Qk mice.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗