A new animal model of human familial hypercholesterolemia, known as Watanabe heritable hyperlipidemic (WHHL) rabbit, has recently become available. Homozygous WHHL-rabbit resembles their human counterparts in having an accumulation of LDL on a low-fat diet, severe fulminant atherosclerosis and a genetic defect in LDL-receptor in all tissues. Using this rabbit, we have been able to study lipoprotein metabolism and to ascertain the accumulation of LDL.
In this report, I want to discuss the following questions :
1. How does the defect or reduction of LDL receptor elevate LDL particles?
2. How can the synthesis of LDL receptor be induced?
3. Which lipoproteins can transform macrophages into foam cells?
4. Is it possible to prevent the progression of atherosclerosis in WHHL rabbits in vivo?

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Humans who have inherited the human class I major histocompatibility allele HLA-B27 have a markedly increases risk of developing the multi-organ system diseases termed spondyloarthropathies. To investigate the role of B27 in these disorders, we introduced the B27 and human β2-microglobulin genes into rats, a species known to be quite susceptible to experimentally induced inflammatory disease. Rats from one transgenic line spontaneously developed inflammatory disease involving the gastrointestinal tract, peripheral and vertebral joints, male genital tract, skin, nails, and heart. This pattern of organ system involvement showed a striking resemblance to the B27-associated human disorders. These results establish that B27 plays a central role in the pathogenesis of the multiorgan system processes of the spondyloarthropathies. Elucidation of the role of B27 should be facilitated by this transgenic model.

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Spontaneously epileptic rats (SER, the double mutants homozygous for zitter and tremor genes), which originated from cross mating between tremor rat strain and zitter rat strain, spontaneously exhibit both absence-like and tonic seizures. In addition, wild jumping or running episodes sometimes occur after the tonic seizures. SER can, therefore, be used as an animal model for human epilepsy. We are going to develop congenic zitter strain (WTC-zi/zi) and new SER (WTC-tm/tm, zi/zi), since genetically defined control strains for SER and ZI (an inbred strain of zitter rats) are not available at present. Then, WTC strain, which derived from TRM (WTC-tm/tm, an inbred strain of tremor rats) will be able to be used as a control strain for the three mutant strains. Development of the absence-like seizure (appearance of 5-7 Hz spike and wave complexes in cortical and hippocampal EEG) and the mode of inheritance were examined in tremor rats and the backcross progeny. The results suggested that the absence-like seizure is semidominantly expressed. Zitter gene has been mapped on the rat chromosome 3 by linkage analysis using biochemical markers, RFLPs and microsatellites. Precise mapping of the epileptic seizurerelated genes should be the first step for gene cloning.

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The spontaneously epileptic rat (SER), a double mutant obtained by mating of the zitter and tremor rats, exhibits absence-like seizures and tonic convulsions without external stimulation from 7-8 weeks of age. These epileptic seizures are not observed in the parental strains except for absence-like seizures in the tremor rat. Histopathological studies of the central nervous system revealed the following abnormalities. The 35-day-old SERs which have never shown seizures had marked vacuole formation and hypomielination in the brainstem and cerebellum. The vacuoles were produced by splitting of myelin sheaths and swelling of dendrites and were related to primary swelling of the astrocytes. Ca²⁺-ATPase activity was low in all parts of the brain, particularly in the molecular layer of the cerebellum. All of the above mentioned changes were exactly similar to the changes observed in the tremor rats. The 2- to 3-month-old SERs with staggering gait and seizures showed focal axonal swelling and advanced vacuole formation in the granular cell layer of the cerebellum in addition to the abnormalities observed at 35 days. Degenerative neurons and spheroidal bodies were observed in the substantia nigra and ventral tegmental nucleus. Calcification of the neuropil was found in the midbrain. These structural abnormalities occurred with a combination of zitter and tremor phenotypes, and the brain areas showing the abnormalities are known to be related to tonic convulsions or absence-like seizures in the several models for epilepsy. Consequently, the SER is believed to be a useful tool for the investigation of the relationship between the morphological changes and epileptic seizures.

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The pathological alterations in the central nervous system (CNS) of spontaneously epileptic rats (SER) were reviewed in comparison with those of zitter (Zi) and tremor (Tm) rats which are original neurological mutants for SER. The main pathological findings were vacuolation and hypomyelination in the CNS. Vacuolation was prominent in SER and Tm, especially in the brain stem and thalamus. Ultrastructurally, vacuoles consisted mainly of swollen astrocytic processes and enlargement of extracellular space, as well as occasional enlargement of periaxonal spaces. Throughout the observation period, there was no inflammatory cell infiltrations nor phagocytotic cells. Vacuolation seemed to be mainly derived from tremor mutation.
On the other hand, hypomyelination seemed to be related to zitter mutation, based on the chronological observation of early myelination in Zi from 1st to 28th days of age. The characteristic findings accompanied with hypomyelination were the presence of aberrant myelin sheaths in addition to a decreased number of myelinated fibers and increased number of radial components whose real significance has been still unknown. Zi revealed another characteristic alteration in oligodendrocytes, which was membranous abnormality associated with nuclear membrane or other intracellular organelles, such as mitochondria or endoplasmic reticulum. The structures of myelin sheath in these three kinds of mutants seemed to be quite normal and the expression of main structural proteins, such as myelin basic protein (MBP), proteolipid protein (PLP) and myelin associated glycoprotein (MAG) were also seemed to be normal.
According to the pathological findings obtained to date, the two different genetic abnormalities (zitter and tremor mutations) interact and synergistically reinforce each other both in clinically and neuropathologically in this double mutant (SER) . To elucidate the etiology and pathogenesis of clinical symptoms and pathological alterations, further neuropathological investigations cooperated with other research fileds, such as genetics, biochemistry, pharmacology, electrophysiology and so on will be required.

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The spontaneously epileptic rat (SER; zi/zi, tm/tm) is the double mutant obtained by mating the tremor rat (TRM; tm/tm) with the zitter rat (ZI; zi/zi), exhibits tonic convulsions and absencelike seizures without external stimulation, and has marked vacuolation and hypomyelination in the brain. Vacuole formation is seen widely in the brain of TRM rat as same as SER. As free radical and its related materials may possibly participate to form vacuole in the brain of SER and TRM rats, free radicals (⋅C, ⋅OH, ⋅H), TBARS level, SOD activity and content of fatty acids were investigated.
During maturation, free radicals and Cu, Zn-SOD activities in the brain of SER did not change, but TBARS levels in cerebellum and pons-medulla oblongata increased. On the other hand, in pons-medulla oblongata of TRM rats, Cu, Zn-SOD activity and ⋅OH radical increased during maturation. In the same region of the 24-week-old TRM rats, TBARS level increased and the content of arachidonic acid (C_{22: 4}) decreased significantly compared with those in WTC rats. These results suggest that vacuole formation may be caused by lipid peroxidation of membrane.

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The spontaneously epileptic rat (SER) is a recently bred epileptic animal model which has seizures resembling absence and tonic seisures in humans from two months of age onwards, with similar electroencephalographic characteristics and responses to various antiepileptic drugs.
In this study, local cerebral glucose utilization (LCGU) in SERs and their parent strains, zitter (ZI) and Kyoto/wistar (KW) rats were investigated by the autoradiographic [¹⁴C] 2-deoxy-glucose method. LCGU of the 8-week-old SERs which had never exhibited the epileptic seizures was decreased in all brain regions examined, but there were no significant differences in the extent of decrement among those regions, in comparison with KW rats. Moreover, there were no differences in LCGU in all regions examined among both SERs and ZI rats. To the contrary, at 13 weeks of age, the interictal LCGU of SERs which exhibited the epileptic seizures was, on the whole, lower than in the other two strains, and in particular, significantly lower LCGU being found in the hippocampus and amygdala.
In local cerebral blood flow (LCBF) measured using I-125-N-isopropyl-iodoamphetamine, although significantly lower LCBF was found in the amygdala of ZI and SER and in temporal cortex of SER when compared with those of KW, there was no difference in other regions tested among these three strains.
These results suggest that the hippocampus and amygdala are the key structures related to the epileptogenic focus of SERs.

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The spontaneously epileptic rat (SER) is a double mutant (zi/zi, tm/tm) obtained by mating zitter homozygote (zi/zi) with tremor heterozygote (tm/ + ) . This animal exhibits both tonic convulsion and absence-like seizures characterized by a sudden appearance of 5-7 Hz spikes and wave complex in cortical and hippocampal EEG. This study was performed to elucidate the usefulness of SER in evaluating of acute and long-term effects of antiepileptic drugs. Moreover, activities of the central inhibitory system and abnormal excitability of neurons related to the epileptic seizures were investigated. (1) From recordings of implanted electrode in cerebral cortex and hippocampus, phenytoin and carbamazepine (agents for tonic-clonic grand mal seizure) inhibited tonic convulsion without affecting absence-like seizures, whereas trimethadione and ethosuximide (agents effective for absence seizure, petit mal epilepsy) suppressed absence-like seizures without any effects on tonic convulsion. Both seizures were inhibited by phenobarbital, valproate and diazepam, agents which are effective for grand and petit mal epilepsy. This antiepileptic profile suggests that tonic and absence-like seizures in SER correspond to human grand and petit mal seizures. Therefore, SER is a useful model for evaluating the acute effects of novel antiepileptics. (2) The group of SER, which were orally administered with 1 % phenobarbital-containing pellet displayed a marked increase in body weight and longer a life span than the control group with a plasma concentration of 35-50 μg/ml. Similar to the futile results of chronic administration of phenobarbital in human absence epilepsy, absence-like seizures in SER were not affected by this drug, although tonic convulsion was inhibited. Long-term effects of valproate (1 and 5 %) were similar to those of phenobarbital except for its efficacy on absence-like seizures. Therefore, SER is also useful for the evaluation of long-term effects of antiepileptics. (3) Both tonic and absence-like seizures in SER were inhibited by TRH and its analog, CNK-602A, and dopamine agonists, methamphetamine and apomorphine. These results suggest that dopaminergic pathways act as an inhibitory system on the seizure-producing mechanism. Further, SER can be used for investigations of the central inhibitory system involved in the regulation of seizures. (4) In hippocampal slice preparations, a single stimulus given to the mossy fiber induced a longlasting depolarization shift with repetitive firings in CA3 field pyramidal neurons of the SER but not zitter or wistar rats. This abnormal excitation of the neurons were completely blocked by verapamil, a calcium channel blocker. These findings suggest that abnormal calcium channel activities in the CA3 pyramidal neurons are involved in the seizures of SER. Thus, SER is a useful animal model for investigating abnormalities related to epileptic seizures.

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