Hiroko Matsushita

Plasticity and injury in the developing brain

The childs brain is more malleable or plastic than that of adults and this accounts for the ability of children to learn new skills quickly or recovery from brain injuries. Several mechanisms contribute to this ability including overproduction and deletion of neurons and synapses, and activity-dependent stabilization of synapses. The molecular mechanisms for activity-dependent synaptic plasticity are being discovered and this is leading to a better understanding of the pathogenesis of several disorders including neurofibromatosis, tuberous sclerosis, Fragile X syndrome and Rett syndrome. Many of the same pathways involved in synaptic plasticity, such as glutamate-mediated excitation, can also mediate brain injury when the brain is exposed to stress or energy failure such as hypoxia-ischemia. Recent evidence indicates that cell death pathways activated by injury differ between males and females. This new information about the molecular pathways involved in brain plasticity and injury are leading to insights that will provide better therapies for pediatric neurological disorders.

Vulnerability to aging in the rat serotonergic system

Abstract Distributional changes of serotonergic fibers associated with aging were demonstrated immunohistochemically. Old rat brains were morphologically characterized by the presence of peculiar features of serotonergic fibers not found in the young adult brain. In 24-month-old rats, these aberrant serotonergic fibers were subdivided into two groups according to morphological alterations: type 1 fibers consisting of thin fibers with moderately enlarged varicosities, and type 2 fibers consisting of much thicker fibers that have even larger varicosities and a tortuous course. These two types of fibers were distributed differentially in the forebrain. Type 1 fibers were found mainly in the striatum and frontoparietal cortex, whereas type 2 fibers were found in the posterior cingulate cortex and dentate gyrus of the hippocampal formation. Both types of aberrant fibers were seen in amygdala, frontoparietal cortex, hypothalamus, and thalamus. In 36-month-old rats, more highly degenerating arborizations were detected, and these aberrant ramifications were classified as follows based on shape as: type 3 fibers consisting of highly arborized thin fibers with a larger number of larger varicosities, and type 4 fibers consisting of thick fibers with abundant larger varicosities. Distributional difference indicated that type 1 fibers progress into type 3 fibers, whereas type 2 develop into type 4 fibers. These findings suggest the possibility that one set of pathological fibers emanate from the dorsal raphe nucleus and the other from the median raphe. Moreover, both two sets of serotonergic fibers show age-related aberrations in their morphology over same time course.

Developmental changes in cerebrospinal fluid concentrations of monoamine-related substances revealed with a Coulochem electrode array system.

The relationship between age and cerebrospinal fluid concentrations of monoamine-related substances, including kynurenine, were investigated using a Coulochem electrode array system, to clarify developmental changes in monoamine-related substances in the human central nervous system. In neurologically normal children, significant inverse correlations with age were observed for the cerebrospinal fluid concentrations of 5-hydroxytryptophan, 5-hydroxyindole-acetic acid, kynurenine, homovanillic acid, 3-methoxy-4- hydroxyphenyl glycol, and 3-O-methyl-dopamine. The concentrations of their precursors, tryptophan and tyrosine, were not related to age. This is the first comprehensive study revealing developmental changes in monoamine-related substances including their precursors and metabolites. (J Child Neurol 2000;15:267-270).

Serotonergic Heterotypic Sprouting in the Unilaterally Dopamine-Depleted Mouse Neostriatum

The effects of unilateral 6-hydroxydopamine (6-OHDA) treatment on striatal serotonin neurons in 12-day-old mice were studied using immunohistochemistry. The unilateral 6-OHDA lesions were evaluated with tyrosine hydroxylase (TH) immunohistochemistry. The majority of the TH-immunoreactive structures disappeared from the substantia nigra and neostriatum on the 6-OHDA lesioned side. However, the density of serotonin fibers was markedly increased throughout the 6-OHDA-depleted neostriatum 1 year later. These results suggest that serotonergic heterotypic sprouting may be permanent.

Treating Neonatal Rats With 6‐Hydroxydopamine Induced an Increase in Voluntary Alcohol Consumption

Brain dopamine (DA) and serotonin (5-HT) neurotransmission have been implicated in the mediation of alcohol-seeking behavior. We examined the effects of treatment of neonatal rats (3 days after birth) with the neurotoxin 6-hydroxydopamine (6-OHDA; 100 μg/10 μl, intracerebroventricularly) on the relationship between the levels of neurotransmitters and alcohol drinking behavior at the age of 14 weeks. 6-OHDA treatment reduced the levels of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens (ACC), frontal cortex, striatum (STR), tegmentum/substantia nigra, and dorsal raphe nucleus. 5-HT levels in the ACC and STR were increased in the 6-OHDA-treated rats. 6-OHDA-treated rats showed increased alcohol consumption. There was a significant change in the ratio of [5-hydroxyindoleacetic acid]/[5-HT] in the ACC and STR of the treated rats, but no difference in the ratio of [DOPAC]/[DA] between the sham-operated controls and treated rats. 6-OHDA-treated rats had dopaminergic dysfunction in the five brain regions related to the reward system, in part, and a decrease in 5-HT turnover, including the accumulation of 5-HT in the ACC and STR. Furthermore, basal extracellular releases of DA and 5-HT of the ACC were significantly lower in the 6-OHDA-treated rats, compared with the controls. It was suggested that alcohol seeking behavior is associated with the alterations of dopaminergic neurons and the release of 5-HT in the mesocorticolimbic system.

Clinical study on localization-related epilepsy in infancy without underlying disorders.

A clinical study of 15 patients without underlying disorders whose first seizures occurred before 1 year of age was performed to determine the characteristics of localization-related epilepsies in infancy. The patients were retrospectively divided into two groups: the seizure-controlled group (10 patients) and the refractory group (five patients). The seizure-controlled group included patients whose seizures were controlled completely within 1 year after onset; the refractory group included all other patients. The characteristics of the refractory group were as follows: (1) interictal electroencephalography showed focal abnormalities, particularly on the left side, and (2) all of the patients exhibited developmental retardation. Even in the seizure-controlled group, 40% of the patients exhibited developmental retardation, and all of them were indistinguishable from patients with benign complex partial epilepsies in infancy at the onset of the seizures. Aggressive treatment should be re-evaluated for early-onset localization-related epilepsies.

Changes in serotonergic neurons in the brain of pyrithiamine-induced acute thiamine-deficient mice

Abstract We examined changes in 5-hydroxytriptamine (5-HT, serotonin) neurons in pyrithiamine-induced thiamine deficiency in mice immunohistochemically. Extensive decreases in the densities of 5-HT-immunoreactive fibers were detected in the lateral septal nucleus, the thalamus, the medial mammillary nucleus, the dorsal and the median raphe nuclei, the raphe obscurus nucleus, the tegmental area, the cerebellum and the vestibular nucleus, though only a small decrease was detected in the inferior colliculus. Most remarkably, degenerative winding fibers were detected between the deep mesencephalic nucleus and the ventral tegmental area. Increases in intensity of 5-HT immunoreactivity in the dorsal raphe nucleus and decreases in the number of 5-HT-immunoreactive cell bodies in the dorsal and the median raphe nuclei were detected. These results demonstrated the differential vulnerability of 5-HT neurons in thiamine-deficient mice. This is the first report to demonstrate changes in 5-HT neurons immunohistochemically throughout the brain of pyrithiamine-induced thiamine deficient mouse.

TRH increases cerebrospinal fluid concentration of kynurenine

We have analyzed changes in cerebrospinal fluid (CSF) concentrations of monoamine-related substances to clarify the mechanism of the antiepileptic action of thyrotropin-releasing hormone (TRH). TRH-tartrate was administered to 14 patients with intractable epilepsy. Before and 2 weeks after TRH administration, CSF was collected and analyzed for tryptophan and tyrosine metabolites. Among monoamine-related substances, only CSF concentrations of kynurenine were increased after TRH therapy. Considering the fact that kynurenic acid acts as antagonist on the NMDA receptor complex, the results of this study may explain at least one of the mechanisms of the effectiveness of TRH therapy for intractable epilepsy.

Developmental Changes in Cerebrospinal Fluid Concentrations of Monoamine-Related Substances in Patients With Dentatorubral-Pallidoluysian Atrophy

Using a Coulochem electrode array system, we investigated the developmental changes of monoamine-related substances in patients with dentatorubral-pallidoluysian atrophy. The patterns observed in the developmental changes of tryptophan, tyrosine, homovanillic acid (HVA), 3-O-methyldopa, and 3-methoxy-4-hydroxyphenyl glycol (MHPG) in patients with dentatorubral-pallidoluysian atrophy are quite different from those in control subjects. These abnormal developmental changes in monoamine-related substances may be implicated in age-related differences in clinical symptoms of dentatorubral-pallidoluysian atrophy. (J Child Neurol 2001;16:79-82).

Efficacy of Thyrotropin‐Releasing Hormone in the Treatment of Intractable Epilepsy

Purpose: Despite rapid advances in the treatment of epilepsy with the introduction of new drugs, the seizures in a number of children with epilepsy remain uncontrollable. Thus a more potent, yet safer therapy is needed. Adrenocorticotropic hormone (ACTH) has been used to treat children with intractable epilepsy, such as West syndrome and Lennox‐Gastaut syndrome. However, ACTH administration is occasionally associated with serious side effects, including immunosuppression, hypertension, and brain shrinkage. Consequently, in this study, the efficacy of an endogenous hormone, thyrotropin‐releasing hormone (TRH), was reevaluated for the treatment of intractable epilepsy.