• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• v.16 no.2
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• pp.153-159
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• 2005

Autistic disorder and other PDD are currently viewed as a largely genetically determined neurodevelopmental disorder, although its underlying biological causes remain to be established. In this review, we examine the available neurodevelopmental literature on autistic disorder and discuss the findings that have emerged. Typical neuropathological observations are rather consistent with respect to the limbic system (increased cell packing density and smaller neuronal size), the cerebellum (decreased number of Purkinje cells) and the cerebral cortex ($>50\%$ of the cases showed features of cortical dysgenesis). However, most of the reported studies had to contend with the problem of small sample sizes, the use of quantification techniques, not free of bias and assumptions, and high percentages of autistic subjects with comorbid mental retardation or epilepsy. Furthermore, data from the limbic system and on age-related changes lack replication by independent groups. It is anticipated that future neuropathological studies held great promise, especially as new techniques such as design-based stereology and gene expression are increasingly implemented and combined, larger samples are analysed, and younger subjects free of comorbidities are investigated.

• Journal of Life Science
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• v.25 no.9
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• pp.1043-1050
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• 2015

Glutamate is one of the principle transmitters in the CNS. Ionotropic receptors of glutamate, selectively activated by N-methyl-D-aspartate (NMDA), play an important role in the processes of cell development, learning, memory, and etc. On the other hand, many studies discovered that over-activation of glutamate receptors leads to neurodegeneration and are known to be implicated in major areas of brain pathology. Any sustained effect of a transient NMDA receptor activation is likely to involve signaling to the nucleus and to trigger coordinated changes in gene expression. Classically, a set of immediate-early genes are induced first; some of genes are by themselves transcription factors that control expression of other target genes. This study provides understanding of changes of inducible transcription factors mRNA levels with RT-PCR by inducing over-activation of NMDA receptor with intraperitoneal NMDA injection. The experimental conditions were varied by 1, 5, 25, and 125 g/ of body weight NMDA and measured transcription factors mRNA levels are Egr-1, c-Jun, JunB, and FosB. Based on result obtained, inducible transcription factors mRNA in NMDA injection to mice with 5 g/body weight showed the greatest change. And ITF mRNA showed greatest change 24 hr after injection. The expression level of JunB mRNA was markedly changed. Up to the present days, no study clearly understood how ITF mRNA affected the apoptosis of purkinje cells in the cerebellum. The current study improves the understanding of the mechanism of apoptosis of purkinje cells in the cerebellum.

• Toxicological Research
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• v.17 no.2
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• pp.73-82
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• 2001

The incidence and distribution of necrotic and apoptotic neural cells, and activated astrocytes in the brain of rats intoxicated intra peritoneally with diisopropylfluorophosphate were investigated. Pyridostigmine bromide (0.1 mg/kg) and atropine methylnitrate (20 mg/kg) were pretreated intramuscularly 30 min and 10 min, respectively, prior to diisopropylfluorophosphate (4-10 mg/kg) administration. Diisopropylfluorophosphate induced severe limbic seizures, early necrotic and delayed apoptotic brain injuries, and rapid astrocytic responses. The necrosis, which was closely related to seizure intensity, was observed as early as 1 hr after intoxication predominently in hippocampal pyramidal cells, cerebellar Purkinje cells and neurons in pyriform/entorhinal cortices, showing malacia of neurophils. In contrast, apoptosis started to appear 12 hr after intoxication in neurons in thalamus, amygdala and neocortex, and ephendymal cells surrounding the 4th ventricle. Since marked apoptosis was induced in rats exhibiting relatively-low seizure intensity, the degree of necrosis and apoptosis was shifted to each type of injury according to the seizure intensity. Activated astrocytes, observed within 1 hr along the limbic system, were suggested to affect the neural injury patterns by producing high level of nitric oxide. However, the distribution of activated astrocytes was not in parallel with those of necrotic or apoptotic injuries, implying that the astrocytic responses resulted from seizure activity rather than neural injuries. Furthermore, astrocytes in malacic tissues disappeared during the severe limbic seizures. Therefore, it would be one of the cautionary notes on the expression of glial fibrillary acidic protein in astrocytes as a biochemical marker of brain injuries following acute exposure to organophosphates.

• Animal cells and systems
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• v.1 no.4
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• pp.589-594
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• 1997

The neuronal voltage-sensitive calcium channels (VSCCs) are multisubunit complexes consisting of $\alpha_1,\;\alpha_2-\delta$ and $\beta$ subunits. Heterologous expression and biochemical studies have shown that the activity of VSCCs is regulated by their $\beta$ subunits in a $\beta$ subunit isoform-specific manner. To elucidate the $\beta$ subunit identity of the P/Q-type calcium channel encoded by an $\alpha_{1A}$ subunit, which is exclusively expressed in the Purkinje and granule cell of the cerebellum, we have examined the spatial and temporal expression patterns of $\beta$ subunits and compared them with those of $\alpha_{1A}$ subunit in the developing rat cerebellum. Reverse transcriptase- polymerase chain reaction (RT-PCR) and Northern blot analysis have shown that $\beta_4$ subunit mRNA was prominently expressed in the cerebellum and much more abundant than any other distinct $\beta$ subunits. RNase protection assay has further demonstrated that the expression of $\alpha_{1A}$ and $\beta_4$ subunits increased during cerebellar development, while the amount of $\beta_2$ and $\beta_3$ mRNAs did not significantly change. In addition, a $\beta_4$ transcript was present in cultured cerebellar granule cells, but not in astrocyte cells, and the level of $\beta_4$ mRNA expression increased gradually in vitro seen as in vivo. Based on the spatial and temporal expression patterns of $\beta_4$ subunit, we conclude that $\beta_4$ may predominantly associate, but probably not exclusively, with the $\alpha_{1A}$ subunit in rat cerebellar granule cells.

• Proceedings of the Korean Society of Developmental Biology Conference
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• 2001.10a
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• pp.14-17
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• 2001

Positional clonging (map-based cloning) of mutations or genetic variations has been served as an invaluable tool to understand in-vivo functions of genes and to identify molecular components underlying phenotypes of interest. Mice homozygous for the cerebellar deficient folia (cdf) mutation are ataxic, with cerebellar hypoplasia and abnormal lobulation of the cerebellum. In the cdf mutant cerebellum approximately 40% of Purkinje cells are ectopically located within the white matter and the inner granule cell layer (IGL). To identify the cdf gene, a high-resolution genetic map for the cdf-gene-encompassing region was constructed using 1997 F2 mice generated from C3H/HeSnJ-cdf/cdf and CAST/Ei intercross. The cdf gene showed complete linkage disequilibrium with three tightly linked markers D6Mit208, D6Mit359, and D6Mit225. A contig using YAC, BAC, and P1 clones was constructed for the cdf critical region to identify the gene. A deletion in the cdf critical region on chromosome 6 that removes approximately 150 kb of DNA selection. cdf mutant mice with the transgenic copy of the identified gene restored the brain abnormalities of the mutant mice. The positional cloning of cdf gene provides a good example showing the identification of a gene could lead to finding a new component of important molecular pathways.

• Proceedings of the KSAR Conference
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• 2001.10a
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• pp.14-17
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• 2001

Positional cloning (map-based cloning) of mutations or genetic variations has been served as an invaluable tool to understand in-vivo functions of genes and to identify molecular components underlying phenotypes of interest. Mice homozygous for the cerebellar deficient folia (cdf) mutation are ataxic, with cerebellar hypoplasia and abnormal lobulation of the cerebellum. In the cdf mutant cerebellum approximately 40% of Purkinje cells are ectopically located within the white matter and the inner granule cell layer (IGL). To identify the cdf gene, a high-resolution genetic map for the cdf-gene-encompassing region was constructed using 1997 F2 mice generated from C3H/HeSnJ-cdf/cdf and CAST/Ei intercross. The cdf gene showed complete linkage disequilibrium with three tightly linked markers D6Mit208, D6Mit359, and D6Mit225. A contig using YAC, BAC, and P1 clones was constructed for the cdf critical region to identify the gene. A deletion in the cdf critical region on chromosome 6 that removes approximately 150kb of DNA was identified. A gene associated with this deletion was identified using cDNA selection. cdf mutant mice with the transgenic copy of the identified gene restored the brain abnormalities of the mutant mice. The positional cloning of cdf gene provides a good example showing the identification of a gene could lead to finding a new component of important molecular pathways.

• Korean Journal of Veterinary Service
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• v.29 no.4
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• pp.469-482
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• 2006

The term 'heat shock protein (Hsps)' was derived from the fact that these proteins were initially discovered to be induced by hyperthermic conditions. In response to a range of stressful stimuli, including hyperthermia, immobilization, UV radiation, amino acid analogues, arsenite, various chemicals, and drugs the mammalian brain demonstrates a rapid and intense induction of the heat shock protein. Moreover, Hsps were expressed on the various pathological conditions including trauma, focal or global ischemia, hypoxia, infarction, infections, starvation, and anoxia. Especially, Hsp25 has a protective activity, facilitated by the ability of the protein to decrease the intracellular levels of reactive oxygen species (ROS) as well as its chaperone activity, which favors the degradation of oxidized proteins. Recently, it has clearly demonstrated that Hsp25 is constitutively expressed in the adult mouse cerebellum by parasagittal bands of purkinje cells in three distinct regions, the central zone (lobule VI-VII) and nodular zone (lobule IX-X), and paraflocculus. The Mongolian gerbil has been introduced into stroke study model because of its unique brain vasculature. There are no significant connections between the basilarvertebral system and the carotid system. This anatomy feature renders the mongolian gerbil susceptible to forebrain ischemia-induced seizure. The present study is designed to examine the pattern of Hsp25 expression in the cerebellum of this animal in comparison with that in mouse.

• Applied Microscopy
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• v.35 no.3
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• pp.165-176
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• 2005

Studies on molecular plasticity of Bermann glia (BG) after harmaline-induced Purkinje cell (PC) degeneration in the rat cerebellum. The intimate structural relationship between BG and PC, evidenced by the sheathing of the PC dendrites by veil-like process from the BG has been suggestive of the close functional relationship between these two cell types. However, little is known about metabolic couplings between these cells. This study designed to investigate molecular plasticity of BG in the rat cerebellum in which PCs were chemically ablated by harmaline treatment. Immunohistochemical examination reveals that harmaline induced PC degeneration causes a marked glial reaction in the cerebellum with activated BG and microglia aligned in parasagittal stripes within the vermis. In these strips, activated BG were associated with upregulaion of metallotheionein, while GLAST and was down regulated, as compared with nearby intact area where both BG are in contact with PCs. The data from this study demonstrate that BG can change their phenotypic expression when BG loose their contact with PCs. It is conceivable that activated BG may upregulate structural proteins, metallothionein expression to use for their proliferation and hypertrophy; metallothionein expression to cope with oxidative stress induced by PC degeneration and microglial activation. On the contrary, BG may down regulated expression of GLAST because sustained loss of contact with PCs would eliminate the necessity for the cellular machinery involved glutamate metabolism. In conclusion, BG might respond man to death of PCs by undergoing a change in metabolic state. It seems possible that signaling molecules released from PCs regulates the phenotype expression of BG. Also ultrastructures in the organelles of normal PC and BG are distinguished by mitochondrial appearance, and distributed vesicles at the synaptic area in the cytoplasm.

• Journal of Veterinary Clinics
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• v.11 no.1
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• pp.485-505
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• 1994

Lead toxicity was evaluated in forty-five cats on a balanced diet, treated with 0(control), 10, 100(low), 1, 000, 2, 000 and 4, 000(high)ppm of lead acetate orally on a body weight basis. The objectives were to describe the gross and histopathologic changes and to demonstrate what tissue lead concentrations correlate with the known dosages of lead. In subclinical lead toxicity, greater than 80% of the absorbed lead was deposited in the bone, whereas in more acute lead toxicity, 42% of absorbed lead was deposited in the bone and 36% and 20% of absorbed lead was deposited in the kidneys and in the liver, respectively. No gross lesions were found in the nervous system. Yellow-brown colored livers appear to be associated with lead toxicity. Neuronal necrosis in the cerebrum was the most predominant histopathologic finding. Astrocytic proliferation in the cerebral gray matter was observed in 1 high dose cat. Gliosis was noted in the cerebral cortex of 6 high dose cats. Two high dose cats had demyelination in the deepest layer of the cortical gray matter of the cerebrum. Extravasation of red cells and cavitation around the vessels were found in the cerebrum of 1 high dose cat. Six high dose cats had degeneration of Purkinje cells in the cerebellum. The microscopic findings in the peripheral nerves were ambiguous. In more acute toxicity, the cats had lead inclusions in the epithelial cells of proximal tubules of the kidneys of 7 cats and hepatocytes of the liver of S cats. These inclusions could be seen wlth H&E, but were more prominent with orcein staining. Two high dose cats had granulomas and connective tissue hyperplasia between tubules of the kidneys. Periportal hepatocyte vacuolization was observed in the liver of 22 cats. Vacuolization of seminiferous tubules and a reduced number of spermatogonia(indicative of reduced spermatogenesis) were found in the testis of 5 treated cats. Cystic ovaries were observed in 3 high dose cats and poor development of oogonia was found in 2 cats. The diagnosis of lead toxicity in cats can be suspected on the basis of the histopathologic lesions described, and can be of value in contributing to a diagnosis. A reliable diagnosis of lead poisoning can be helped utilizing tissue lead analysis(post molten)

• Journal of Biomedical Engineering Research
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• v.38 no.3
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• pp.123-128
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• 2017

Background and aims: The KCNQ1 S140G mutation involved in $I_{ks}$ channel is a typical gene mutation affecting atrial fibrillation. However, despite the possibility that the S140G gene mutation may affect not only atrial but also ventricular action potential shape and ventricular responses, there is a lack of research on the relationship between this mutation and ventricular fibrillation. Therefore, in this study, we analyzed the correlation and the influence of the KCNQ1 S140G mutant gene on ventricular fibrillation through computer simulation studies. Method: This study simulated a 3-dimensional ventricular model of the wild type(WT) and the S140G mutant conditions. It was performed by dividing into normal sinus rhythm simulation and reentrant wave propagation simulation. For the sinus rhythm, a ventricular model with Purkinje fiber was used. For the reentrant propagation simulation, a ventricular model was used to confirm the occurrence of spiral wave using S1-S2 protocol. Results: The result showed that 41% shortening of action potential duration(APD) was observed due to augmented $I_{ks}$ current in S140G mutation group. The shortened APD contributed to reduce wavelength 39% in sinus rhythm simulation. The shortened wavelength in cardiac tissue allowed re-entrant circuits to form and increased the probability of sustaining ventricular fibrillation, while ventricular electrical propagation with normal wavelength(20.8 cm in wild type) are unlikely to initiate re-entry. Conclusion: In conclusion, KCNQ1 S140G mutation can reduce the threshold of the re-entrant wave substrate in ventricular cells, increasing the spatial vulnerability of tissue and the sensitivity of the fibrillation. That is, S140G mutation can induce ventricular fibrillation easily. It means that S140G mutant can increase the risk of arrhythmias such as cardiac arrest due to heart failure.