Miyuki Sadamatsu

Trimethyltin syndrome as a hippocampal degeneration model: temporal changes and neurochemical features of seizure susceptibility and learning impairment

The effects of trimethyltin on the hippocampus were investigated in terms of changes in histology, depth electroencephalography, learning acquisition and memory retention, choline acetyltransferase and neuropeptides, and seizure-induced c-fos messenger RNA expression. The results were as follows. (1) Morphologically, trimethyltin produced a progressive loss of hippocampal CA3 and CA4 pyramidal cells, starting from four days after peroral treatment with trimethyltin hydroxide (9 mg/kg), as described previously. (2) Neurophysiologically, the increased seizure susceptibility to pentylenetetrazol treatment reached a maximum at four days post-trimethyltin and then declined after five days post-trimethyltin. The maximal seizure susceptibility at four days post-trimethyltin was confirmed by the immediate and long-lasting appearance of spike discharge in the hippocampus. However, this was not verified by the expression of c-fos messenger RNA in the hippocampus, which was comparable between trimethyltin-treated and control rats. (3) Behaviorally, the time-courses of aggression and learning impairment were similar to that of the seizure susceptibility. (4) Neurochemically, trimethyltin treatment caused changes of neurochemical markers, which were manifested by the elevation of neuropeptide Y content in the entorhinal cortex, and of choline acetyltransferase in the hippocampal CA3 subfield. Trimethyltin may offer potential as a tool for investigations on the relationship between neuronal death in the hippocampus and the development of seizure susceptibility and learning impairment. Alterations in glucocorticoids, glutamate and neuropeptides may all contribute to the manifestation of the trimethyltin syndrome.

Perinatal bisphenol A affects the behavior and SRC-1 expression of male pups but does not influence on the thyroid hormone receptors and its responsive gene.

Bisphenol A (BPA) has been shown to interfere with thyroid hormone receptors (THRs) and to influence the expression of THR-responsive elements in vivo and in vitro, while some studies reported hyperactivity induced by BPA treatment. In the present study, our purpose was to investigate the effect of BPA exposure on behavioral alteration and its mechanism of action, especially focusing on the thyroid hormone pathway. Significant sexual difference on behaviors was observed in perinatal BPA exposure, as manifested by hyperactivity and impaired spatial learning/memory in male pups after matured. Dams treated with 0.1mg/l BPA showed transient hypothyroidism, while male pups were found to exhibit a transient hyperthyroidism followed by hypothyroidism. Furthermore, significant up-regulated expression levels of mRNA and protein of SRC-1 in the hippocampus were observed in male pups by 0.1mg/l BPA treatment. However the expression of THRalpha/beta and RC3/neurogranin were not affected by BPA treatment. These results indicate that perinatal BPA exposure at a very low level may influence thyroid function and then consequently affects brain development, but at the same time, suggest that thyroid hormone receptor may not be a direct target of BPA action, but instead, another factor may be involved in this action.

Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions.

Paroxysmal kinesigenic dyskinesia (PKD (MIM128000)) is a neurological disorder characterized by recurrent attacks of involuntary movements. Benign familial infantile convulsion (BFIC) is also one of a neurological disorder characterized by clusters of epileptic seizures. The BFIC1 (MIM601764), BFIC2 (MIM605751) and BFIC4 (MIM612627) loci have been mapped to chromosome 19q, 16p and 1p, respectively, while BFIC3 (MIM607745) is caused by mutations in SCN2A on chromosome 2q24. Furthermore, patients with BFIC have been observed in a family concurrently with PKD. Both PKD and BFIC2 are heritable paroxysmal disorders and map to the same region on chromosome 16. Recently, the causative gene of PKD, the protein-rich transmembrane protein 2 (PRRT2), has been detected using whole-exome sequencing. We performed mutation analysis of PRRT2 by direct sequencing in 81 members of 17 families containing 15 PKD families and two BFIC families. Direct sequencing revealed that two mutations, c.649dupC and c.748C>T, were detected in all members of the PKD and BFIC families. Our results suggest that BFIC2 is caused by a truncated mutation that also causes PKD. Thus, PKD and BFIC2 are genetically identical and may cause convulsions and involuntary movements via a similar mechanism.

Review of animal models for autism: implication of thyroid hormone

ABSTRACT    Autism is a behaviorally defined disorder associated with characteristic impairments in social interactions and communication, as well as restricted and repetitive behaviors and interest. Its prevalence was once thought to be 2/10 000, but recently several large autism prevalence reviews revealed that the rate of occurrence was roughly 30/10 000. While it has been considered a developmental disorder, little is certain about its etiology. Neuroanatomical studies at the histological level in the brains of autistic patients provide many arguments in the etiology of autism. Results from postmortem and imaging studies have implicated many major structures of the brain including the limbic system, cerebellum, corpus callosum, basal ganglia and brainstem. There is no single biological or clinical marker for autism. While several promising candidate genes have been presented, the critical loci are yet unknown. Environmental influences such as rubella virus, valproic acid, and thalidomide exposure during pregnancy are also considered important, as concordance in monozygotic twins is less than 100% and the phenotypic expression of the disorder varies widely. It is thus hypothesized that non‐genetic mechanisms contribute to the onset of autistic syndrome. In light of these ambiguities, hope is held that an animal model of autism may help elucidate matters. In this article, we overview most of the currently available animal models for autism, and propose the rat with mild and transient neonatal hypothyroidism as a novel model for autism.

Cytokines participate in neuronal death induced by trimethyltin in the rat hippocampus via type II glucocorticoid receptors.

We investigated the role of IL-1alpha and IL-1beta expressed in the reactive gliosis following hippocampal damage induced by trimethyltin (TMT). IL-1alpha immunoreactivity was expressed earlier in small glial cells on day 4 post-TMT, while IL-1beta expression was obvious in large swollen glial cells on day 14 post-TMT. Both IL-1alpha and IL-1beta immunoreactivities were double-labeled with astrocyte marker, vimentin, but not with a microglia marker, OX-42. The expression of both IL-1alpha/beta was enhanced by adrenalectomy (ADX) prior to TMT administration. Corticosterone (CORT) or dexamethasone (DEX) supplementation not only cancelled effects of ADX, but also partially reversed TMT-induced enhancement of IL-1alpha/beta expressions. These changes coincided with TMT-induced neuronal death in CA3 pyramidal cells of the hippocampus. It is suggested that IL-1alpha/beta expressed in reactive astrocytes participate in TMT neurotoxicity via type II glucocorticoid receptors.

Altered brain contents of neuropeptides in spontaneously epileptic rats (SER) and tremor rats with absence seizures

Immunoreactive- (IR-) somatostatin (SRIF), neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) contents were investigated in the brain of tremor rats with absence-like seizure and spontaneously epileptic rats (SER), which is a genetically defined double-mutant (zi/zi, tm/tm) obtained by mating zitter homozygote (zi/zi) with tremor heterozygote (tm/+) and shows both absence-like seizure and tonic convulsions. Increased levels of IR-NPY and IR-CRF were observed in several regions including the amygdala and hippocampus in homozygous SER compared to heterozygous SER (zi/zi, tm/+ or +/+). Homozygous tremor rats (tm/tm) showed lower levels of IR-NPY and IR-CRF contents mainly in the hippocampus and mesolimbic system (entorhinal and pyriform cortex and nucleus accumbens) than heterozygous tremor rats. IR-SRIF contents of homozygous SER were higher in frontal cortex than heterozygous SER and in amygdala than homozygous tremor rats. No change of IR-SRIF between groups was noted in the hippocampus among brain structures underlying epileptogenicity. The results suggest that the change of neuropeptide levels, most conspicuous in NPY among three peptides tested, may be involved in the phenotypical manifestation of seizures in SER and tremor rats, and that the development of tonic convulsion and absence seizures may be differently associated with the change of brain neuropeptide levels.

The 24‐hour Rhythms in Plasma Growth Hormone, Prolactin and Thyroid Stimulating Hormone: Effect of Sleep Deprivation

Twenty‐four hour secretory rhythms of growth hormone (GH), prolactin (PRL) and thyroid stimulating hormone (TSH) were investigated in 9 normal adult men by means of serial blood sampling at 30 min intervals. The profiles of pituitary hormones were compared in 6 subjects between in normal nocturnal sleep condition and in delayed sleep condition. Plasma GH was measured with use of highly sensitive enzyme immunoassay (EIA) recently developed. Plasma TSH was also evaluated by highly sensitive time‐resolved fluorometric immunoassay (TR‐FIA). Time series analysis of plasma GH and PRL was performed by auto‐ and cross‐ correlation and spectral analysis.

Familial Paroxysmal Kinesigenic Choreoathetosis : An Electrophysiologic and Genotypic Analysis

Summary: Purpose: We report a pedigree of familial paroxysmal kinesigenic choreoathetosis (PKC) in which five of 18 members are affected. The pathophysiologic basis for PKC is still uncertain; reflex epilepsy versus dysfunction of basal ganglia. We examined (a) whether there were ictal discharges during the attacks, and (b) a linkage between PKC and possible DNA markers linked to several familial epileptic or movement disorders.

Trimethyltin intoxication induces marked changes in neuropeptide expression in the rat hippocampus

In situ hybridization and immunocytochemistry were applied to investigate changes in the expression of somatostatin, neuropeptide Y, neurokinin B, cholecystokinin, dynorphin, and Met‐enkephalin in the rat hippocampus after administration of a single peroral dose of trimethyltin hydroxide (9 mg/kg). Two time intervals were investigated: 5 days after trimethyltin treatment, when CA3 damage becomes manifest and is associated with increased aggression, seizure susceptibility, and memory deficit, and 16 days after trimethyltin, when neuronal damage is almost maximal and seizure susceptibility is declining. Robust but transient increases of neuropeptide Y, neurokinin B, and Met‐enkephalin mRNA levels were revealed in the granule cell layer of the dentate gyrus and increased neuropeptide Y and neurokinin B immunoreactivities were found in mossy fibers. In reverse, dynorphin mRNA and immunoreactivity were decreased transiently in the dentate gyrus and mossy fibers, respectively. Strong over‐expression of NPY mRNA was also observed in hilar interneurons and in CA1 and CA3 pyramidal cells as well as in the cortex at 5 days postdosing. Cholecystokinin‐ or neurokinin B‐containing basket cells were preserved, while somatostatin‐bearing interneurons were damaged by trimethyltin exposure. These neurochemical changes induced by trimethyltin intoxication strikingly parallel to those observed in animal models of temporal lobe epilepsy and may reflect activation of endogenous protective mechanisms. It is also suggested that hilar interneurons respond differently to trimethyltin exposure, for which neuropeptides are valuable markers. Synapse 29:333–342, 1998.

Paroxysmal kinesigenic choreoathetosis: From first discovery in 1892 to genetic linkage with benign familial infantile convulsions

Paroxysmal kinesigenic choreoathetosis (PKC) is presently clearly designated as a familial movement disorder with autosomal dominant inheritance. We identified a family of PKC, in which 6 out of 23 members were affected, and 4 of the affected members had a history of infantile convulsions. Thus, this family was also considered as a case of infantile convulsions with paroxysmal choreoathetosis (ICCA). Video-EEG monitoring of two affected members suggested that PKC is less likely to be a form of reflex epilepsy, despite the existence of a history of infantile convulsions. Linkage analysis on eight Japanese families, including this family, defined the locus of PKC within the pericentromeric region of chromosome 16. ICCA and a form of autosomal dominant benign familial infantile convulsions (BFIC) were both mapped to the same or nearby region for PKC on chromosome 16. Additionally and quite unexpectedly, the locus of wet/dry ear wax (cerumen) was found to be located in the same region. Lastly, it was pointed out that the priority of the first discovery of PKC in the world should go to a Japanese psychiatrist, Shuzo Kure (1865-1932), who published the first detailed and almost complete description of a male patient with PKC in a Japanese medical journal in 1892.