Contents of several amino acids in the cerebellum, brain stem and cerebrum of the 'staggerer', 'weaver' and 'nervous' neurologically mutant mice.

The content of glutamate, GABA, aspartate, glycine and alanine was determined in the cerebellum, brain stem and cerebrum of three different mutant mice which have been named ‘staggerer’, ‘weaver’ and ‘nervous’ on the basis of neurological symptoms. In the ‘staggerer’ and ‘weaver’ mutants there is an almost complete absence of granule cells in the cerebellar cortex while in the ‘nervous’ mutant there is a loss of Purkinje cells (and to a lesser extent a loss of granule cells) in the cerebellar cortex. In the cerebellum of the ‘weaver’ mutant, the content of glutamate was signficantly lower (P < 0.025) than control values (8.77 ± 0.76 vs 12.0 ± 1.3 μmol/g tissue wet wt) and the contents of GABA and glycine were significantly greater than normal levels. In the cerebellum of the ‘staggerer’ mutant, the content of glutamate was significantly lower (6.62 ± 0.70 μmol/g) and the contents of glycine and alanine significantly higher than control values. In the cerebrum and brain stem regions of the staggerer mutant, weaver mutant and the normals the contents of the five amino acids were the same. The contents of glycine and alanine in the cerebellum, GARA and glycine in the brain stem and GABA and alanine in the cerebrum of the nervous mutants were higher than control values. The data are discussed in terms of a possible role for glutamate functioning as an excitatory transmitter when released from the cerebellar granule cells.     

POSTNATAL CHANGES IN FREE AMINO ACID,DNA, RNA AND PROTEIN CONCENTRATIONS OF MINIATURE SWINE BRAIN1

Postnatal developmental characteristics of miniature swine brain were evaluated through the first 9 weeks of age. Differential growth rates of cerebrum, cerebellum and brain stem were defined in terms of DNA, RNA, protein and free amino acid concentrations at ages 5, 21, 35 and 63 days. Within the experimental conditions provided, hyperplasia ceased just prior to ages 21, 35 and 63 days for cerebellum, brain stem and cerebrum, respectively. An additional cerebral growth spurt, observed between weaning at age 35 days and sacrifice at age 63 days, may be indicative of impaired brain development due to inadequate nutrition provided by the dam's milk. Developmental changes in mean concentrations of brain free amino acids varied with anatomical area and differed somewhat from those of other species previously reported. For example, mean cerebral concentrations of aspartic acid, γ-aminobutyric acid and asparagine + glutamine decreased significantly (P < 0·05) with age and mean glutamic acid concentration was 5 times that of taurine.     

Effect of subchronic exposure to arsenic on levels of essential trace elements in mice brain and its gender difference

The interactions of toxic metals with essential metals may result in disturbances in the homeostasis of essential elements. However, there are few reports about toxic effect of arsenic (As) on the levels of essential trace elements in the central nervous system. To investigate whether subchronic exposure to As disturbs levels of main essential trace elements in the brain of mice and whether the gender difference in the response to As are altered, the concentrations of As, Iron (Fe), copper (Cu), selenium (Se), zinc (Zn) and Chromium (Cr) in the cerebrum and cerebellum of mice exposed to As subchronically were examined by inductively coupled plasma-mass spectrometry (ICP-MS). The gender difference in the changed levels of these essential trace elements was also statistically analyzed. The concentration of As was significantly higher in the cerebrum or cerebellum of mice exposed to As than that in control group (P < 0.05). It indicates that As can accumulate in brain of mice after subchronic exposure. The concentrations of Fe, Se and Cr in the cerebrum or cerebellum were significantly lower in mice exposed to As than those in control group (P < 0.05). On the contrary, the concentration of Cu in the cerebrum or cerebellum was significantly higher in mice exposed to As (P < 0.05). Our results indicate that subchronic exposure to As may decrease the levels of Fe, Se and Cr or increase the level of Cu in the brain of mice. Moreover, the significant gender difference was found relative to the effect of As on concentration of Se in cerebrum and concentrations of Cu and Se in cerebellum of mice. Therefore, more experiments are required to further understand mechanisms whereby As interacts with essential elements in brain and induces the gender difference.     

Determination of free d-aspartic acid,d-serine and d-alanine in the brain of mutant mice lacking d-amino-acid oxidase activity

A simple and precise method for the simultaneous determination of free d-aspartic acid, d-serine and d-alanine in mouse brain tissues was established, using a reversed-phase HPLC system with widely used pre-column derivatizing reagents, o-phthaldialdehyde and N-t-butyloxycarbonyl-l-cysteine. With the present method, the contents of these three d-amino acids in hippocampus, hypothalamus, pituitary gland, pineal gland and medulla oblongata as well as cerebrum and cerebellum of mutant mice lacking d-amino-acid oxidase activity were determined and compared with those obtained for control mice. In both mice, extremely high contents of d-serine were observed in forebrain (100–400 nmol/g wet tissue), and the contents were small in pituitary and pineal glands. While, d-serine contents in cerebellum and medulla oblongata of mutant mice were about ten times higher than those in control mice. In contrast, d-alanine contents in mutant mice were higher than those in control mice in all brain regions and serum.     

Elevated immunoreactive-somatostatin levels in the brain of ataxic mutant mice

Immunoreactive-somatostatin (IR-SRIF) levels were investigated in the brain of 4 types of ataxic mice (Rolling Mouse Nagoya, Weaver, PCD, Staggerer) with different cerebellar pathologies. IR-SRIF concentrations (ng/mg) were found to be significantly elevated in both cerebellum and cerebrum of all ataxic mutant mice, IR-SRIF (ng/organ) was found to be increased in the cerebellum and cerebrum in Rolling Mouse Nagoya and PCD compared with control mice. The gel-filtration profile (Sephadex G-50) in the cerebellar extracts of Rolling Mouse Nagoya proved to be identical to that of control mice. Three peaks of IR-SRIF were found to be uniformly elevated in Rolling Mouse Nagoya, with the highest peak coinciding with authentic somatostatin-14. The present results suggest that elevated levels of IR-SRIF in the brain may play a role in the mechanism underlying the manifestation of ataxia in ataxic mutant mice, especially in Rolling Mouse Nagoya and PCD.     

Fundamental study on ataxic mice (wriggle mouse Sagami)

Wriggle mouse Sagami (WMS), a newly discovered BALB/C mouse strain, is characterized by its locomotor instability, abnormal gait pattern and neck wriggling. Although the growth of WMS mice is delayed, compared with normal BALB/C mice, the brain size corresponds to the relatively smaller body weight. In gross or histological examinations no local atrophy appears in the cerebrum, cerebellum, brain stem or spinal cord. The c-GMP level in the WMS cerebellum is decreased, but the c-AMP level is normal. The ataxic gait is not improved significantly by the administration of thyrotropin releasing hormone (TRH). These results indicate that the mechanism inducing ataxia and abnormal gait pattern in WMS may be different from those in other genetically-determined ataxic mice, e. g., Rolling mouse Nagaya (RMN), PCD, Staggerer and Reeler.     

Factors Contributing to the Poor Myelination in the Brain of the Snell Dwarf Mouse

Abstract: Conventional histological examination of the pituitary does not distinguish Snell dwarf mutants (dw/dw) from their normal littermates (+/?) in the neonatal stage. However, immunohistochemical examination of pituitaries of litters born to heterozygous Snell parents revealed that in approximately 25% of the glands examined, the number of positive cells was very low in the neonatal stage. We attempted to delineate the events resulting in the poor myelination in the brain of the Snell dwarf mouse, and to devise an immunohistochemical method for identifying the mutant neonate. Differences in the brain weights of the dw/dw and +/? mice first became apparent on the 10th day of age, and from this time on no further increase in the weight of the dwarf mouse brain was recorded. Increase in CNPase activity was found to be suppressed in the cerebrum and brain stem throughout the developmental stage, but not in the other parts of the brain. The yield of isolated myelin decreased by 58% in the mutant mouse, but CNPase activity was equivalent to that of control myelin. Differences in DNA content per cerebrum from the dw/dw and +/? mice first became apparent on the 10th day of age. Henceforth, the dw/dw mice showed no further increase, although the +/? mice continued to increase. [³H]Thymidine incorporation into the DNA fraction in vivo on the 7th day of age, when glial cell proliferation in the cerebrum is most active, was suppressed to about 50% of the control level in all parts of the dwarf brain. These findings indicate that the poor myelination found in the mutant cerebrum is a hypomyelination due to reduced oligodendroglial proliferation caused by lack of circulating growth hormone.     

Studies on thyrotropin releasing hormone in cerebellar ataxia mutant mouse brain

The effects of cathecholamine on the regional TRH distribution in the brain was studied in rolling mouse Nagoya (RMN) and non-affected C3H mice. TRH was extracted from the hypothalamus, brain stem, cerebellum, and cerebrum one hour after i.p. injection of the precursor or inhibitors of cathecholamine. TRH was distributed throughout the brain of both affected and non-affected mice; however, in RMN, TRH levels were lower in the hypothalamus and higher in other areas. 1-Dopa caused a decrease of TRH in the brain stem but no change in other regions in the RMN brain, whereas it caused an increase in TRH levels in all areas of the C3H brain. Fusaric acid increased TRH in the hypothalamus of RMN and decreased it in the cerebellum; alpha-MPT also caused a decrease in the TRH level in the cerebellum. Reserpine increased the TRH level in the hypothalamus and decreased it in the cerebrum. From these results, it appears that cerebellar ataxia in RMN does not result from a decrease in the TRH, which is actually increased in the cerebellum. Catecholamine had different effects on TRH levels in RMN and the controls; this might be due to the excess accumulation of noradrenaline in the RMN brain.     

Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase

Metabolite profiling in succinate semialdehyde dehydrogenase (SSADH; Aldh5a1-/-) deficient mice previously revealed elevated gamma-hydroxybutyrate (GHB) and total GABA in urine and total brain and liver extracts. In this study, we extend our metabolic characterization of these mutant mice by documenting elevated GHB and total GABA in homogenates of mutant kidney, pancreas and heart. We quantified beta-alanine (a GABA homolog and putative neurotransmitter) to address its potential role in pathophysiology. We found normal levels of beta-alanine in urine and total homogenates of mutant brain, heart and pancreas, but elevated concentrations in mutant kidney and liver extracts. Amino acid analysis in mutant total brain homogenates revealed no abnormalities except for significantly decreased glutamine, which was normal in mutant liver and kidney extracts. Regional amino acid analysis (frontal cortex, parietal cortex, hippocampus and cerebellum) in mutant mice confirmed glutamine results. Glutamine synthetase protein and mRNA levels in homogenates of mutant mouse brain were normal. We profiled organic acid patterns in mutant brain homogenates to assess brain oxidative metabolism and found normal concentrations of Kreb's cycle intermediates but increased 4,5-dihydroxyhexanoic acid (a postulated derivative of succinic semialdehyde) levels. We conclude that SSADH-deficient mice represent a valid metabolic model of human SSADH deficiency, manifesting focal neurometabolic abnormalities which could provide key insights into pathophysiologic mechanisms.     

Two proteins associated with cerebellar hypoplasia in jaundiced Gunn rats

Two cerebellar proteins with apparent molecular weights of 250,000 (GR-250) and 50,000 (GR-50) are closely associated with cerebellar hypoplasia in jaundiced homozygous Gunn rats. These proteins, found in Gunn rat cerebellum (4–60 days of age) and cerebrum as well as staggerer mouse cerebellum, were studied with electrophoretic techniques. After 8 days of life, GR-250 decreased and GR-50 increased in the homozygous Gunn rat cerebellum. The pI's of GR-250 and GT-50 were 4.7–5.8 and 4.6–4.9, respectively, and the former protein was shown to bind to Concanavalin A. A comparative study between cerebella of Gunn rats and staggerer mice revealed that GR-250 and P₄₀₀, a protein generally thought to be characteristic of the Purkije cells, were identical. Evidence was also obtained showing that GR-250 was present in the Gunn rat cerebrum. GR-50 was not detectable in the staggerer mouse cerebellum but instead, a protein (MW 47,000) was found to be increased in the mutant mouse cerebellum.     

Determination of regional distributions of phenylethylamine andmeta-andpara-tyramine in rat brain regions and presence in human and dog plasma by an ultra-sensitive negative chemical ion gas chromatography-mass spectrometric (NCI-GC-MS) method

Using a new ultrasensitive method the trace biogenic amines, phenylethylamine,meta-tyramine andpara-tyramine have been quantitated in brain regions obtained from a single rat. Phenylethylamine concentrations in ng/g wet tissue (mean±std. error) were as follows: caudate 2.71±0.73, hypothalamus 0.45±0.15, cerebellum 0.09±0.02, olfactory bulb 0.35±0.11, stem 0.13±0.03, hippocampus 0.20±0.11, cortex 0.69±0.13 and the rest (remainder of the brain) 2.81±0.41. Mean whole brain was 1.23±0.19 ng/g, in agreement with previous measurements.meta-Tyramine concentrations (ng/g) were: caudate 2.69±0.19, hypothalamus 0.32±0.16, cerebellum 0.07±0.04, olfactory bulb 0.09±0.04, stem 0.04±0.01, hippocampus, 0.07±0.02, cortex 0.18±0.15 and the rest 0.15±0.06, with a mean whole brain value of 0.26±0.05 ng/g andpara-tyramine concentrations were: caudate 8.99±1.60, hypothalamus 0.93±0.13, cerebellum 0.78±0.27, olfactory bulb 0.70±0.13, stem 0.90±0.36, hippocampus 0.40±0.06, cortex 1.78±0.28 and the rest 2.38±0.12 and mean whole brain was 1.90±0.25 ng/g. In human plasma the concentrations of the three amines were found to be 31.3±3.4 pg/ml, 5.3±1.6 pg/ml and 66.0±9.9 pg/ml respectively and in dog blood 95.3±4.6 pg/ml, 24.0±7.6 pg/ml and 486±43 pg/ml respectively. When monoamine oxidase inhibitors were added to the blood immediately after collection there were no significant increases in the amine levels indicating that MAO-B is not present in plasma in significant quantities.     

Alteration of brain type N-glycans in neurological mutant mouse brain

We have previously detected two brain-specific and development-dependent N-glycans [H. Shimizu, K. Ochiai, K. Ikenaka, K. Mikoshiba, and S. Hase (1993) J. Biochem. 114, 334-338]. In the present study we attempted to analyze specific N-glycans detected in neurological mutant mice. N-glycans in cerebrum and cerebellum obtained from 3-week-old neurological mutant mice (jimpy, staggerer, and shiverer) were compared with those obtained from normal mice. N-glycans liberated from the cerebrum and cerebellum by hydrazinolysis-N-acetylation were pyridylaminated, and pyridylamino derivatives of N-glycans thus obtained were separated into neutral and five acidic fractions by anion exchange chromatography. PA-N-glycans in each fraction were compared with those obtained from normal mice by reversed-phase HPLC, and the following results were obtained. The ratio of the two brain-type N-glycans, Manalpha1-3(GlcNAcbeta1-2Manalpha1-6)(GlcNAcbeta1-4)Manbeta1-4GlcNAcbeta1-4(Fucalpha1-6)GlcNAc (BA-1) to GlcNAcbetaManalpha1-3(GlcNAcbeta1-2Manalpha1-6)(GlcNAcbeta1-4)Manbeta1-4GlcNAcbeta1-4(Fuca1-6)GlcNAc (BA-2), was higher in staggerer mice than other mutant mice and normal mice. Sia-Gal-BA-2, triantennary N-glycans, and bisected biantennary N-glycans were found in the cerebellum of shiverer and staggerer mice but not in normal or jimpy mice. High-mannose type N-glycans were not altered in mutant mice brains. The amounts of disialylbiantennary N-glycans and disialylfucosylbiantennary N-glycans were lower in jimpy mouse cerebellum than in normal mouse cerebellum, but were higher in shiverer mouse. Some alterations of N-glycans specific to mutations were successfully identified, suggesting that expression of component(s) of the N-glycan biosynthetic pathway was specifically affected in neurological mutations.     

Microcephalic cerebrum with hypomyelination in the growth hormone-deficient mouse (lit)

To determine whether GH has an independent action on cerebral development, we examined the central nervous system of thelittle mouse (lit), a promissing model of isolated growth hormone deficiency. Our findings are (A); the weights of two parts of thelit brain were significantly less than those of the normal controls, 81.5% less for the cerebrum, and 81.6% for the cerebellum, (B): the total DNA content was reduced to approximately 80% in the cerebrum and 84% in the cerebellum compared to those of the normal controls, (C); the total RNA content was also reduced in the cerebrum and cerebellum, proportional to the reduction in DNA, (D); CNPase activity was reduced selectively in the cerebrum of thelit mouse (74.4% of the normal control), and (E); thelit mice exhibited a strikingly reduced level of activity with an indistinct diurnal periodicity. These results indicate that GH has independent actions on cerebral development, especially on glial cell proliferation as a precondition of myelin formation.Dedicated to Professor Yasuzo Tsukada.     

Net sulfatide synthesis, galactosylceramide sulfotransferase and arylsulfatase A activity in the developing cerebrum and cerebellum of normal mice and myelin-deficient jimpy mice

Net sulfatide synthesis, galactosylceramide sulfotransferase (EC 2.8.2.11) and arylsulfatase A (EC 3.1.6.1) activities were measured in two brain regions, cerebrum and cerebellum, of normal and jimpy mice during postnatal development. In normally myelinating mice, two phases of increasing rates of net sulfatide synthesis were observed, the first coinciding with oligodendrocyte proliferation and the second with myelination. Net sulfatide synthesis was quantitatively higher in the cerebellum than in the cerebrum. In both brain regions, the developmental patterns of net sulfatide synthesis were related to the activity patterns of both galactosylceramide sulfotransferase and arylsulfatase A. In jimpy mice, a neurological mutant showing hypomyelination in brain, the first phase of net sulfatide synthesis was preserved in both brain regions and galactosylceramide sulfotransferase and arylsulfatase A activities were normal up to 12 days. However, during the phase in which myelination occurred in controls, the net sulfatide synthesis in both brain regions of jimpy mice was zero or even negative. The sulfatide deficit was larger in the cerebellum than in the cerebrum. In both mutant brain parts, galactosylceramide sulfotransferase activity increased up to 12 days showing about 50% of the maximal activities observed in normal brain regions. Thereafter up to 15 days, enzyme activity decreased to about 25% of that of controls and remained low in both brain regions. The developmental patterns and the activities of arylsulfatase A were, however, normal in the cerebrum and cerebellum of jimpy mice. These results suggest that the enzyme activities and the developmental patterns of galactosylceramide sulfotransferase and arylsulfatase A as measured in vitro reflect to a high degree their functional activity in vivo. Furthermore, sulfatide degradation by arylsulfatase A seems to be important in regulating net sulfatide synthesis during normal and impaired myelination.     

Brain histogenesis in vitro: Reconstruction of brain tissue from dissociated cells

Summary Comparative studies of the aggregative behavior of cells dissociated from different areas of embryonic chick and mouse brains show that each of the regionally differentiated lobes (cerebrum, optic tectum, and cerebellum), and the stem areas (diencephalon and medulla), form characteristic aggregates distinctive in size and shape. Bispecific co-aggregates are produced by commingling dissociated mouse cerebrum cells with chick cells from various brain regions, or from non-nervous tissues; the size of these co-aggregates and the extent of internal sorting out of cell types is closely related to the degree of homology between the interacting cell populations, e.g. co-aggregates of the closely homologous mouse and chick cerebral cell types contain homogeneous tissue fabrics of intermingled mouse and chick cells. Cell surface constituents involved in selective recognition and association of nerve cells were sought and cell-free supernatant preparations were obtained from short-term monolayer cultures of embryonic cerebrum cells (of either mouse or chick origin) which caused a striking, specific enhancement of aggregation of homologous cerebrum cells. These materials had no such effect on heterologous tissues tested: optic tectum, cerebellum, medulla, neural retina, liver, kidney or limb bud. These findings are discussed in relation to control mechanisms governing normal brain histogenesis and to the specificity of neural associations. This work was supported by United States Public Health Service research grant HD-01253 to Aron Moscona and by the Louis Block Fund of the University of Chicago.     

Cerebral, cerebellar, and brain stem gangliosides in mice susceptible to audiogenic seizures

Abstract— The quantitative and qualitative distribution of gangliosides was investigated in the cerebrum, cerebellum and brain stem of audiogenic seizure resistant (C57BL/6J) and susceptible (DBA/2J) mice at 21 days of age. The concentration of gangliosides (μg/unit weight) was higher in the DBA cerebrum and brain stem, but lower in the DBA cerebellum compared to the concentration in C57 mice. In general, the brain water content was lower in DBA mice than in C57 mice. The distributions of a number of gangliosides were found to be different between the two strains and the differences were often in the same direction across the three brain regions. The most consistant and significant difference in ganglioside pattern observed between the strains was the higher concentration of G_M1 in all three regions of the DBA brain. These results suggest that DBA mice have a more heavily myelinated CNS than C57 mice. The relationship of these observations to inherent audiogenic seizure susceptibility is discussed.     

Myelin Lipids in the Developing Cerebrum, Cerebellum, and Brain Stem of Normal and Undernourished Children

Abstract: The developmental lipid profiles in the human cerebrum, cerebellum and brain stem are presented, with special reference to galactolipids as myelin markers to trace myelination in the three main parts of the human CNS. A group of undernourished children were also studied to test the vulnerability of myelinogenesis in the different regions of the human brain. Myelination was well advanced in the brain stem with regard to the other brain regions, a fact reflected in the much higher concentration of myelin lipids in the brain stem of the human foetus of 26 weeks of gestational age. The cerebrum, on the other hand, had the lowest galactolipid concentration during the prenatal period, galactolipid levels in the cerebellum being four times higher. From just before the end of gestation the accretion of galactolipids accelerated enormously in the cerebrum, whereas it slowed down considerably in the cerebellum. Consequently, in relation to prenatal levels galactolipids increased most rapidly in the cerebrum, followed by the cerebellum and finally by the brain stem. These regional differences were in clear contrast to data from the rat, as was the finding that only the cerebrum of undernourished children had a galactolipid concentration significantly decreased with respect to normal values. A relationship between the different myelination patterns in the human and the rat and the distinct vulnerability of myelinogenesis in the two species is suggested.     

Diffusion of intracerebrally injected [1-14C]arachidonic acid and [2-3H]Glycerol in the mouse brain

[2-³H]Glycerol and [1-¹⁴C]arachidonic acid were injected into the region of the frontal horn of the left ventricle of mice and were distributed rapidly throughout the brain. After 10 sec, most of the radioactive fatty acid was found in the hemisphere near the injection site; after 10 min, it was recovered in similar proportions in the cerebellum and brain stem. [2-³H]Glycerol showed a heterogeneous distribution, with most of the label remaining in the left hemisphere even after 10 min. On a fresh weight basis, cerebrum, cerebellum, and brain stem were found to contain similar amounts of labeled glycerol. However, the amount of [1-¹⁴C]arachidonate in cerebrum was only 50% of that recovered from cerebellum or brain stem. Brain ischemia or a single electroconvulsive shock reduced the spread of the label, producing an accumulation of radioactivity in the injected hemisphere, except for an increase in [2-³H]glycerol in the brain stem during ischemia. Despite the significant decrease in available precursor in the cerebellum and brain stem after electroshock, the amount of label incorporated into lipids was not altered in these areas and only slightly diminished in the cerebrum.     

Factors contributing to cerebral hypomyelination in the growth hormone-deficientlittle mouse

We attempted to delineate the events leading to hypomyelination in the brain of thelittle mouse, a promising murine model of isolated growth hormone deficiency. At 20 days of age, the mutant mouse brain weighed less than its normal counterpart, and this difference in brain weight persisted. Increase in CNPase activity was found to be suppressed in the cerebrum throughout the developmental stage, but not in the other parts of the brain. Differences in cerebral DNA content between thelittle and normal mice first became apparent on the 10th day of age. Thereafter, the rate of increase in thelittle brain consistently lagged behind the normal. [³H]Thymidine incorporation into the DNA fraction in vivo on the 7th day of age, when glial cell proliferation in the normal cerebrum is most active, was approximately half that of the controls in all parts of thelittle brain. These findings indicate that the hypomyelination of the mutant cerebrum might result from reduced oligodendroglial proliferation due to growth hormone deficiency.     

Brain DNA metabolism in myelin deficient mutant jp,jpmsd and qk mice

We studied metabolism of brain DNA in three myelin deficient mutants qk, jp and jp^msd mice. The DNA content, the in vivo incorporation of [¹⁴C]thymidine in DNA and the activity of acid DNase in tissues (cerebellum and cerebrum) from normal littermates and affected mice were compared. The results showed that neither the DNA content, the incorporation of [¹⁴C]thymidine in DNA nor the activity of acid DNase in brain were altered in qk affected mice. In jp^msd mice, however, the DNA content as well as the incorpation of thymidine in DNA were reduced in both cerebellum and cerebrum, but the activity of acid DNase was reduced in cerebrum only. In jp mice, although the DNA content was reduced in both cerebellum and cerebrum, the incorporation of thymidine in DNA and the activity of acid DNase were reduced in cerebrum only. The data suggest a) that in qk mutants DNA metabolism and hence cell (glial) proliferation is not affected; b) that in jp^msd mutants DNA synthesis, and thus the cell proliferation is reduced in cerebellum as well as in cerebrum of the affected mice and c) that in jp mutants the synthesis of DNA and the cell proliferation is reduced in cerebrum but not in cerebellum.