Histological and ultrastructural features in the early stage of Purkinje cell degeneration in the cerebellar calcification (CC) rat.

The cerebellar calcification (CC) rat is a new neurodegenerative mutant with severe Purkinje cell loss and symmetrical calcifications in the cerebellar cortex manifesting ataxia: lack of coordination in body movements. In the present study, histopathological features were examined in the Purkinje cell degeneration in postnatal homozygous suckling rats without clinical signs, which were genotyped by microsatellite markers. In addition, the calcified Purkinje cells were investigated ultrastructurally and elemental analysis was performed on the deposits. Body weight of the homozygous (cc/cc) rats was already slightly lower compared with the heterozygotes (cc/+) in the neonatal stage. The degeneration of the Purkinje cells in the cc/cc rats was recognized obviously in lobules VI, VII, VIII and IX from 14 days after birth, a few days before the appearance of the ataxic behavior. The Purkinje cells in the region along the fissure between the VIII and IX lobule areas were intensely positive for periodic acid-Schiff reaction specific to glycoconjugates, and in this region, calcium depositions were weakly positive for von Kossa's stain. Electron microscopy also revealed that the calcified Purkinje cells possessed numerous electron-dense bodies containing inclusions with cystic structures such as vesicles, mitochondria and lysosomes, and these bodies were mainly composed of calcium and phosphorous. These findings suggest abnormal storage of glycoconjugates might be a trigger of Purkinje cell degeneration and serves as a matrix for accumulation of calcium phosphate in the cerebellum of CC rats.

A novel mutation vf causing abnormal vacuoles in the central nervous system maps on rat chromosome 8.

Body-tremorous rats were found in a colony of WTC-tm rats and a new coisogenic mutant strain void of the tm mutation was established. Histological analysis revealed that these rat mutants had abnormal vacuoles in the red nucleus of the midbrain, the reticular formation in the brain stem, and the white matter of the cerebellum and spinal cord. Electron microscopic observation showed many irregular myelin-bound vacuoles and degenerated oligodendroglia. Genetic analysis indicated that the presence of the abnormal vacuoles in the central nervous system (CNS) is controlled by a recessive gene named "vacuole formation (vf)" on chromosome (Chr) 8, and that this gene is also involved in the appearance of body tremors. Comparative maps suggested that the mouse and human orthologs would be located on Chr 9 (43-48 cM) and Chr 6 (328-370 cR3000), respectively. Since similar mutations have not been mapped yet around these regions, the authors believe this novel rat mutation will allow the discovery of a new function of these particular genes that is involved in the development and maintenance of the CNS.

The pck rat: a new model that resembles human autosomal dominant polycystic kidney and liver disease.

BACKGROUND: The pck rat is a recently identified model of polycystic kidney disease (PKD) and liver disease (PLD) that developed spontaneously in the rat strain Crj:CD/SD. Its pattern of inheritance is autosomal recessive. METHODS: To characterize this new model, we studied pck rats derived from F9 breeding pairs from Charles River Japan and control Sprague-Dawley rats. Blood and tissues (kidneys, liver, and pancreas), obtained from these rats at 1, 7, 21, 70, and 182 days of age, were used for biochemical determinations, light and electron microscopy, and immunohistochemistry. RESULTS: The pck rats develop progressive cystic enlargement of the kidneys after the first week of age, and liver cysts are evident by day 1. The renal cysts developed as a focal process from thick ascending loops of Henle, distal tubules, and collecting ducts in the corticomedullary region and outer medulla. Flat and polypoid epithelial hyperplasia were common in dilated tubules and cysts. Apoptosis was common and affected normal, as well as dilated tubules, but less frequently cysts lined by flat epithelium. The basement membranes of the cyst walls exhibited a variety of alterations, including thinning, lamellation, and thickening. Focal interstitial fibrosis and inflammation were evident by 70 days of age. Segmental glomerulosclerosis and segmental thickening of the basement membrane with associated effacement of the podocyte foot processes were noted in some rats at 70 days of age. The PKD was more severe in male than in female pck rats, as reflected by the higher kidney weights, while there was no gender difference in the severity of the PLD. Mild bile duct dilation was present as early as one day of age. With age, it became more severe, and the livers became markedly enlarged. Even then, however, there was only a mild increase in portal fibrosis, without formation of fibrous septae. Slight elevations of plasma blood urea nitrogen levels were detected at 70 and 182 days of age. CONCLUSIONS: The pck rat is a new inherited model of PKD and PLD with a natural history and renal and hepatic histologic abnormalities that resemble human autosomal dominant PKD. This model may be useful for studying the pathogenesis and evaluating the potential therapies for PKD and PLD. The identification of the pck gene may provide further insight into the pathogenesis of autosomal dominant PKD.

The Charles River "hairless" rat mutation is distinct from the hairless mouse alleles.

The Charles River (CR) "hairless" rat is one of the autosomal recessive hypotrichotic animal models actively studied in pharmacologic and dermatologic research. Despite its widespread use, the molecular basis of this monogenic mutation remains unknown, and the skin histologic features of this phenotype have never been described. However, the designation "hairless" has been used as an extension of the hairless mouse (hr) nomenclature on the basis of the clinical absence of hairs in both phenotypes. We present a description of the histopathologic changes in heterozygous and homozygous CR hairless rat mutants during the first month of life. The postnatal homozygous rat skin was characterized by abnormal keratinization of the hair shaft and formation of a thick and dense layer of corneocytes in the lower portion of the epidermal stratum corneum. This layer prevented the improperly keratinized hair shaft from penetrating the skin surface. Starting from the latest stages of hair follicle (HF) development, obvious signs of HF degeneration were observed in homozygous skin. This process was extremely rapid, and by day 12, mainly atrophic HFs with abnormal or broken hairs were present in the skin. Therefore, the mutation in the CR rat abrogates cell proliferation in the hair matrix and affects keratinocyte differentiation in the HF and interfollicular epidermis, a phenotype that is completely distinct from hr/hr. To test whether the CR rat harbored a mutation in the hr gene, we analyzed the coding region of this gene and consensus intron splice site sequences in mutant rats and found no mutation, further supporting phenotypic evidence that the hairless phenotype in CR rats is not allelic with hairless. Finally, using intragenic polymorphisms, we were able to exclude homozygosity at the hairless locus by use of genotypic analysis. Thus, morphologic analysis of successive stages of phenotype development in the CR hairless rat, together with definitive molecular studies, indicate that this mutation may be unique among the other hypotrichotic rat mutations.

Aberrant trajectory of entorhino-dentate axons in the mutant Shaking Rat Kawasaki: a Dil-labelling study.

The Shaking Rat Kawasaki (SRK) is a neurological mutant that exhibits abnormalities of cell migration and lamination, with many similarities to the mouse reeler mutant. We recently used lamina-specific antibody staining to show that despite severe aberrations in the laminar organization of the SRK dentate gyrus, the entorhinal terminal field in the outer dentate molecular layer appeared relatively normal (Woodhams & Terashima, 1999, J. Comp. Neurol. 409 p57). However, neurofilament immunostaining suggested that entorhino-dentate afferents take an abnormal trajectory in reaching their appropriate targets, the granule cells dendrites. In the present study, anterograde tracing with the carbocyanine dye 1, 1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) has been used to delineate directly the path that entorhinal axons take to the dentate gyrus, confirming that in SRK entorhinal axons do indeed reach their appropriate terminal fields in the molecular layer, with laminar segregation between projections from the lateral and medial entorhinal cortices. However, these fibres fail to cross the hippocampal fissure between the subiculum and the dentate gyrus, coursing instead parallel to it until they curve round the deepest point of the fissure in field CA3. Similar findings were seen in the murine reeler mutant. Insertion of DiI crystals into the entorhinal cortex of neonatal rats also retrogradely labelled the developmentally transient Cajal-Retzius cells at the hippocampal fissure; these survive for longer in SRK than in normal littermates. The presence of a marked astrogliosis at the SRK hippocampal fissure may play a part in determining the abnormal trajectory taken by entorhino-dentate afferents in this mutant.

Effect of partial pancreatectomy on beta-cell mass in the remnant pancreas of Wistar fatty rats.

Wistar fatty rat, which has been established by transferring the fa gene of Zucker fatty rat to the Wistar Kyoto rat, has many features in common with human NIDDM. It exhibits hyperglycemic obesity with hyperinsulinemia and insulin resistance. It is unclear, however, whether a defect in the beta-cell proliferation is related to the onset of diabetes mellitus together with insulin resistance in this model rat. To determine this, we compared non-fasting plasma glucose levels, insulin content and beta-cell mass in the remnant pancreas of Wistar fatty rats with those in their diabetic-resistant lean counterparts after a 70% partial pancreatectomy. We also examined whether such a defect, if present, could be improved by either phlorizin or nicotinamide. We further investigated if there were any differences in these parameters between the phenotypically identical but genotypically different Wistar lean rats with a gene type of homogeneous Fa/Fa and that of heterogeneous Fa/fa. Male rats, 6 weeks of age, were allocated at random into two groups: 70% pancreatectomy (Px) and sham-pancreatectomy (sham). A sustained hyperglycemia was evident in the Px Wistar fatty rats after surgery, which was accompanied by a reduction of insulin content and beta-cell mass in the remnant pancreas. The changes in insulin content and beta-cell mass were unaffected by restoration of normoglycemia, induced by phlorizin injection. The administration of nicotinamide partially ameliorated the sustained hyperglycemia by a slight but not significant increase in beta-cell mass. No discernible difference in the above parameters was observed between the Wistar lean rats with Fa/Fa and those with Fa/fa. These findings suggest that Wistar fatty rats have a poor capacity for proliferation of pancreatic beta-cells, which causes the onset of overt diabetes along with insulin resistance due to extreme obesity.

Fate of developing astrocytes in the optic nerve of the myelin-deficient rat.

There is considerable debate on the development of a glial cell line in the rat optic nerve, which is characterized by the specific expression of the A2B5 and HNK-1 epitopes. This cell line has been assumed to give rise to oligodendrocytes and so-called type 2 astrocytes. However, it is doubtful that the latter cell type really exists in vivo. In the present study, we have addressed this question by investigating the development of astrocytes in the myelin-deficient (md) rat, which is characterized by dysmyelination and loss of oligodendrocytes. Defective oligodendrocytes were observed by the third postnatal day, well before the generation of type 2 astrocytes. Consequently, the number of type 2 astrocytes was reduced in cultures prepared from optic nerves of md rats vs. controls. This finding was not paralleled in vivo; i.e., no dying astrocytes were observed in md sections by conventional electron microscopy. However, immunoreactivity against the HNK-1 epitope was enhanced in md compared to control sections. Ultrastructurally, HNK-1 immunoreactivity was detected predominantly on the axonal surface at astroaxonal contact sites, which were found only at the nodes of Ranvier within controls but extended to the whole axonal surface in md animals. Only a minor portion of the immunoreactivity derived from glial cells, presumably from oligodendrocytes at the paranodal region in controls. Thus, the HNK-1 epitope is not a useful antigen for distinguishing astrocytes in the rat optic nerve. Accordingly, our results do not provide evidence for the existence of specialized type 2 astrocytes in vivo. In vitro, these cells are probably only oligodendrocytes that mimic some astroglial features if grown in serum-containing media.

Hemodynamic and biochemical characteristics of the aorta in the WKY, SHR, WKHT, and WKHA rat strains.

This study was designed to characterize the hemodynamic and biochemical properties of the abdominal aorta in four genetically related inbred rat strains that express genetic hypertension and hyperactive behavior in varying combinations. These include (1) the spontaneously hypertensive rat (SHR), which is hypertensive, hyperactive, and hyperreactive to stress; (2) Wistar-Kyoto (WKY) rats, which express none of these traits; (3) WKHT rats, which are hypertensive but not hyperactive; and (4) WKHA rats, which are hyperactive and hyperreactive to stress, but normotensive. Together, these four strains allowed us to examine the structural and functional changes in the aorta in the hypertensive SHR, the most widely used animal model of genetic hypertension, while controlling for the variables of hyperactivity and hyperreactivity that are also expressed in the SHR. Four groups of animals of both sexes were studied: (1) WKY, n = 101, (2) WKHA, n = 33, (3) WKHT, n = 91, and (4) SHR, n = 28. Blood pressure (BP) was determined by tail plethysmography as well as direct intraarterial monitoring under anesthesia. Fixed specimens were prepared for histologic analysis and the wall thickness determined morphometrically. Quantification of soluble tissue protein, elastin, and collagen in the aortic tissue was determined by measuring leucine (leu), hydroxyproline (HP/leu), and desmosine (DES/leu). The hypertensive strains (SHR and WKHT) had significantly higher tail BP than the normotensive strains (WKY and WKHA)-WKY: 128.7 +/- 22.3; WKHA: 126.7 +/- 14.6; WKHT: 162.8 +/- 21.2; SHR: 164.2 +/- 36.1 (p < 0.0001). Additionally, intraaortic diastolic BP and mean BP were higher in SHR rats than in WKHT. Morphometric studies showed the media thickness in the SHR rats was significantly greater than in the WKY and WKHA rats and no different than in the WKHT rats. Significantly less of the aortic wall protein was present as elastin in the hypertensive rats (SHR and WKHT), as well as the hyperactive rats (WKHA), compared to rats that had neither trait (WKY). These studies provide new information regarding aortic structure and function in genetic hypertension using inbred strains to control for the hyperactivity/hyperreactivity traits that coexist with hypertension in the SHR. They reveal that hypertensive aortas have altered matrix proteins that cannot be explained simply on the basis of blood pressure alone.

Anatomic and physiologic characterization of the WF/PmWp-"fz" (fuzzy) rat.

The WF/PmWp-"fz" rat is an inbred strain of hypotrichotic rat derived from a Wistar Furth colony. This strain, also known as the "fuzzy rat," has been used for dermal toxicity research; however, little is known about its longevity and age-related physiologic and pathologic changes. Presented are basic anatomic and physiologic parameters, collected for each sex at five ages, including hematologic and clinical biochemical profiles, organ and body weights, and a characterization of gross and histopathologic findings.

Absence of normal sexual dimorphism of the genitofemoral nerve spinal nucleus in the mutant cryptorchid (TS) rat.

Sexual dimorphism of the genitofemoral nerve spinal nucleus has been demonstrated in normal rodents. Calcitonin gene-related peptide is a neurotransmitter, present in the genitofemoral nerve, that has been implicated in the regulation of gubernacular migration and inguinoscrotal testicular descent. A combination of retrograde fluorescent labelling of the genitofemoral nerve and immunohistochemistry for calcitonin gene-related peptide was used in 1-3-day-old mutant TS rats with 85% incidence of congenital cryptorchidism and an absence of the normal sexual dimorphism of the genitofemoral nerve spinal nucleus was demonstrated. There was no significant difference between male and female nuclei with respect to fluorescent-labelled neurones as well as those immunoreactive for calcitonin gene-related peptide, in contrast to an obvious sexual dimorphism present in normal control animals. This lack of normal sexual dimorphism of the genitofemoral nerve nucleus is likely to be important in the pathogenesis of cryptorchidism in this animal model.

Neuroanatomical characterization of a new mutant rat with dopamine depletion in the substantia nigra.

A new mutant rat strain with movement disorders has arisen spontaneously in a closed colony of Albino-Swiss rats at the Department of Anatomy, Glasgow University. The animals possess a progressive locomotor disorder which is first apparent at around post-natal day 10. We here report that tyrosine hydroxylase immunocytochemistry demonstrates that these mutants have profound depletions in dopaminergic systems in the substantia nigra and corresponding areas of neostriatum.

Pathological characteristics of mucopolysaccharidosis VI in the rat.

The histological and electron microscopical characteristics of the pathology of rats with arylsulphatase B-deficient mucopolysaccharidosis (mucopolysaccharidosis VI; MPS VI) were investigated. In affected animals, intracytoplasmic vacuoles were prominent in chondrocytes, the macrophage system, cardiac valve fibroblasts, cornea, connective tissues, vascular smooth muscle cells and uterine stromal cells. Tissues containing glucosaminoglycans stored in lysosomes were positive to Mowry's colloidal iron and alcian blue stains. By electron microscopy, the lysosomes were seen to be distended by electron lucent or fine fibrillary storage material, and lysosomal storage was also detected in the endothelial cells of the arteries and cornea. In the central and peripheral nervous system abnormalities were restricted to the connective tissue. Lesions in the affected rats resembled those described in human and feline mucopolysaccharidosis VI. These results indicate that MPS VI of the rat may be a useful animal model for human MPS VI (Maroteaux-Lamy syndrome).

Neuronal degeneration in the striatum of the groggy rat: a new mutant with a movement disorder.

A new mutation displaying abnormal movement was obtained in the progeny of a female Wistar rat which had been given 10 mg/kg methylnitrosourea at an early stage of the gestational period. Genetic studies revealed that the character is inherited by an autosomal single recessive gene, and we designated this mutation groggy (gene symbol gr). The abnormal movement of the groggy rat was first apparent around postnatal day 15, while the histological studies revealed the appearance of numerous necrotic neurons in the striatum of the groggy rat on postnatal days 60 and 120.

Pathological and laboratory findings in LEC/Otk rats that spontaneously develop hepatic injury.

The LEC strain of rats that spontaneously develops hepatic injury has been introduced into specific pathogen-free (SPF) conditions (SPF-LEC/Otk). The present communication describes the clinical and pathological features of the SPF-LEC/Otk rats. The characteristic features of these animals are as follows: (i) Jaundice develops in almost all rats with increase in the P-GPT level; (ii) The animals show episodes of jaundice, a high P-GPT level and liver cell necrosis, but only slight inflammatory cell infiltration; (iii) The liver cells show characteristic microvesicular fatty changes; (iv) The P-GPT level shows increases, first at 18 weeks and then at 25 weeks of age; (v) The rats show immunological disorders, such as deficiency of immunoglobulins, especially IgG1, and of helper T cells; (vi) Infectious agents such as viruses do not seem to be involved, although this possibility cannot be absolutely excluded; (vii) The immunological disorders are not directly associated with the occurrence of liver cell necrosis; and (viii) The pattern of inheritance (autosomal single-recessive trait) of the disease strongly suggests that it is due to a genetic metabolic disorder.

Mast cells and fibrosis in compartments of lymph nodes of normal, gnotobiotic, and athymic rats.

Reports vary on the amount and distribution of mast cells in lymph nodes. We analysed the mast-cell population in compartments of nodes of diverse sites, from euthymic and athymic animals of various ages. Nodal mast cells were few in young animals, occurring mostly in medullary sinuses. Aging is often accompanied by a moderate increase of nodal mast cells. In compartments of a few nodes of some aged athymic and euthymic animals, the mast cells were greatly increased in the extrafollicular zone overlying medulla directly. In certain cases, this great increase was accompanied by pronounced mast-cell degranulation and by fibrosis in the mast cell-rich extrafollicular zone. It is suggested that the mast cells of medullary sinuses relate to non-immunological events, while those of the lymphoid parenchyma relate to elements that can induce humoral immune responses or are somehow involved in nodal processes of such responses. It is further suggested that an occasional emergence, with aging, of a deficiency of particular humoral immune responses may induce an excessive increase of cortical mast cells, and that activities of the resulting dense mast-cell population contribute to the onset of fibrosis.

Quantitative fine structure of capillaries in subregions of the rat subfornical organ.

The differentiated cytology across subregions of the rat subfornical organ (SFO) prompted our hypothesis that ultrastructural features of capillary endothelial cells would vary topographically and quantitatively within this small nucleus. We used electron microscopic and computer-based morphometric methods to assess fine structural dimensions of the capillary endothelium in four distinct subregions of the SFO from Long-Evans and homozygous Brattleboro rats. Three types of capillary were present. Type III capillaries (resembling those of endocrine glands) had an average wall thickness of 0.17 microns, 54% thinner than those of Type I and II capillaries. Pericapillary spaces around Type III capillaries measured 56 microns2, 100% larger than for Type I vessels (resembling those of skeletal muscle). Only Type III capillaries contained fenestrations (9 per microns2 of endothelial cell) and were the predominant type of capillary in central and caudal subregions of the SFO. Type I capillaries, prevalent in the transitional subregion between the central and rostral parts of the SFO, had 10 cytoplasmic vesicles per micron2 of endothelial cell area, a number not different from that of Type III capillaries but 3x the frequency found in Type II vessels. Type II capillaries (those typical of "blood-brain barrier" endothelium) had low vesicular density (3 per microns2), no fenestrations, and no pericapillary spaces. Luminal diameters and the densities of mitochondria and intercellular junctions were not different among capillary types or subregions in the SFO. Furthermore, there were no morphometric differences for any capillary dimensions between Long-Evans and Brattleboro rats.(ABSTRACT TRUNCATED AT 250 WORDS)

[Electron microscopic and morphometric research on the development of the outer segments of the photoreceptor cells in mutant Campbell rats with hereditary retinal dystrophy]. / Elektronno-mikroskopicheskoe i morfometricheskoe issledovanie razvitiia naruzhnykh segmentov fotoretseptornykh kletok u mutantnykh krys Campbell s nasledstvennoi distrofiei setchatki.

Development of rod outer segment (ROS) in the posterior area of the retina in normal (GR) and mutant Campbell rats with inherited retinal dystrophy was studied using transmission electron microscopy and morphometry. In both strains of rats primitive cilia appear first after birth and their number progressively increases up to postnatal day 9. The first ROS membrane disks (MD) appear at postnatal day 5. Originally MD are randomly oriented but later they acquire a regular arrangement. At day 7 MD occupy about 14% area of posterior retina in transverse sections in Campbell rats versus 7% in normal animals. By day 9 MD occupy about 35% area in the same region of the retina in both lines of rats. The retina of 15-day-old rats possesses the definitive number of differentiated ROS. The data obtained show that during the period between birth and eyelid opening ROS morphogenesis in Campbell rats is not slow or disturbed as compared with that in normal rats.

Projections from the superior colliculus to the ventral lateral geniculate nucleus in the hereditarily microphthalmic rat.

Projections from the superior colliculus (SC) to the ventral lateral geniculate nucleus (LGNv) were studied in hereditarily microphthalmic and normal rats by means of wheatgerm agglutinin conjugated with horseradish peroxidase (WGA-HRP). Unilateral injection of a tracer into the LGNv in normal rats revealed WGA-HRP positive neurons on both sides of the SC. In the ipsilateral SC, most of the labeled neurons were distributed in the upper part of the stratum opticum (SO) and the lower part of the stratum griseum superficiale (SGS). A few labeled neurons were also found in the same layers of the contralateral SC. After unilateral injections of the tracer into the LGNv of microphthalmic rats, labeled neurons appeared in similar layers of the SC on both sides. However, the number of labeled neurons in the ipsilateral SC decreased to 30% of normal, whereas on the contralateral side these neurons were apparently more numerous than those in normal rats. The soma size of the labeled SC neurons in microphthalmia was not significantly different from normal. These results indicate fundamentally that tecto-LGNv projecting neurons exist in microphthalmic rats despite the fact that they lack optic nerve afferents. Furthermore, the present results, taken together with our previous results, indicate that the diminution in the number of tecto-LGNd neurons was severest (3%), the tecto-LGNv neurons less severe (30%) and the tecto-LP neurons least severe (50% of that of normal).

Electron-microscopic study on the anterior pituitary gland of spontaneous dwarf rats.

The spontaneous dwarf rat is a novel experimental model animal on the study of pituitary dwarfism. The fine structure of the anterior pituitary cells was studied in the immature and mature dwarf rats. Pituitary glands were removed from 5-, 10-, 20-day-old immature dwarfs, adult (45 days-16 weeks) dwarfs and normal 3-month-old rats and processed for electron-microscopic observation. In the control animals, growth hormone cells were readily identified by their ultrastructural characteristics, such as the presence of numerous electron-dense secretory granules, 300-350 nm in diameter, well developed rough endoplasmic reticulum and a prominent Golgi complex. In contrast, growth hormone cells were not found in the anterior pituitary gland of the spontaneous dwarf rat at any age examined. Other pituitary cell types, i.e., luteinizing hormone/follicle stimulating hormone, thyroid stimulating hormone, adrenocorticotropic hormone and prolactin cells, appeared similar in their fine structure to those found in the control rats. In the pituitary gland of dwarf rats, a number of polygonal cells were observed either with no or relatively few secretory granules. The rough endoplasmic reticulum was arranged in parallel cisternae and the Golgi complex was generally prominent in these cells. In addition, many were found to have abundant lysosomes. A few minute secretory granules were occasionally observed; however, the immunogold technique failed to localize growth hormone or prolactin in the granules. The nature of these cells remained obscure in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Purkinje cell abnormalities and synaptogenesis in genetically jaundiced rats (Gunn rats).

The course of cytological abnormalities and synaptogenesis of Purkinje cells were investigated in the culmen of cerebella from homozygous Gunn rats with hereditary hyperbilirubinemia from postnatal day 7 to adulthood (5-10 months old). The affected Purkinje cells were abundant at day 7. A large number of Purkinje cells reached the fully advanced stage of degeneration during the ensuring 16 days and disappeared between days 12 and 30. The Purkinje cells remaining at day 30 were less affected and recovered by the adult stage. Various abnormalities in Purkinje cell synaptogenesis with the parallel fibers, climbing fibers, and basket and stellate cell axons were observed. Primitive junctions between parallel fibers and Purkinje dendritic shafts were often found in adulthood. The parallel fiber boutons lacking postsynaptic partners and facing astrocytic processes were often noted from day 18 to adulthood. The persistence of such presynaptic elements suggests some mechanisms for stabilizing the synaptic elements once they have been formed. Many of the parallel fiber synaptic boutons with or without their postsynaptic partners were enlarged and were assumed to be transsynaptically affected by Purkinje cell damage. A number of climbing fiber synapses with perisomatic process of Purkinje cells, which are transient in normal synaptogenesis, were present at day 30 and a few of them were still found even in adulthood. Basket and stellate cell synapses were often found in abundance on the remaining Purkinje cells in adulthood, though they were not frequently encountered during the development period.