CNS Pathology in the Neurological Mutant Rats Zitter, Tremor and Zitter-Tremor Double Mutant (Spontaneously Epileptic Rat, Ser)

Abstract

The pathological alterations in the central nervous system (CNS) were examined in three kinds of mutant rat; the zitter (zi/zi; Zi), the tremor rat (tm/tm; Tm) and the spontaneously epileptic rat (SER) which is a double mutant carrying both zitter and tremor genes. Two major alterations demonstrated in these mutants were hypomyelination and vacuolation or spongy degeneration. Hypomyelination was observed predominantly in SER and to a lesser extent in Zi, and was accompanied by a redundant or aberrant myelin sheath formation in addition to a decreased number of myelinated fibres. This appeared to be related to the occurrence of tremor. There was no abnormality in the structure of the myelin lamellae and oligodendrocytes or any destruction of myelin sheaths by phagocytic cells. The number of radial components in CNS myelin was increased almost equally in Zi, Tm and SER. Vacuolation was prominent in SER and Tm, especially in the brainstem and thalamus. Zi also developed mild vacuolation with advancing age. Vacuolation seemed to be related to the epileptic phenomena in SER and Tm. Vacuoles consisted mainly of swollen astrocytic processes and enlargement of the extracellular space, as well as occasional enlargement of periaxonal spaces. Thus both pathological findings--the hypomyelination derived from the zitter mutation with tremor, and the vacuolation from the tremor mutation with epileptic symptoms--were mutually exaggerated in SER. It is postulated that the two different genetic loci with zi and tm mutations interact and synergistically reinforce each other both clinically and pathologically in SER.

Myelin Lipid Abnormalities in the Aspartoacylase-Deficient Tremor Rat

“…Animal models with inactivated ASPA have proved useful in the study of this condition, as with the knockout mouse that was shown to have morphologically abnormal myelin [5]. Similarly, the tremor rat, employed in this study, which possesses a natural ASPA mutation, was shown to have hypomyelination, vacuolation along with spongy degeneration of white matter [26], and in addition loss of oligodendrocytes [27]. Use of these animals as research tools has opened a valuable window for study of the specific contributions of ASPA-mediated acetyl formation to myelin lipid synthesis.…”

The Myelin Vacuolation (mv) Rat with a Null Mutation in the Attractin Gene

“…This observation suggested that the severity of vacuolization correlates with the expressed levels of Atrn mRNA and indicated Atrn mRNA was found widely distributed throughout the CNS; a very high level of expression was observed in the olfactory system, some limbic structures, brain stem, cerebellum, and spinal cord in rats (Lu et al, 1999). Severe vacuolization was found in the brain stem, cerebellum, and spinal cord, whereas less mild lesions were observed in the olfactory system and hippocampus in both the rat mutants Atrn mv /Atrn mv and Atrn zi /Atrn zi (Kondo et al, 1991a(Kondo et al, , 1991b(Kondo et al, , 1992. Although the Atrn mRNA expression pattern and the severity of vacuolization are roughly matched, some differences existed in particular regions of the CNS.…”

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

“…In order to address this possibility with our polyclonal ASPA antibodies, we tested antibody binding to brain and kidney tissues from the Tremor rat, an ASPA-null mutant (Kondo et al, 1991) (see section 3 below). This mutant lacks the entire ASPA gene sequence, so no ASPA protein is produced.…”

“…Tremor rats exhibit muscular tremors starting at about 2 weeks of age, which give way to absence-like seizure activity in later development. Pathology in the CNS involves white matter spongiform degeneration and hypomyelination (Kondo et al, 1991). Similarly, homozygous ASPA −/− knockout mice exhibit subcortical and white matter vacuolation.…”