Elsevier

Pediatric Neurology

Volume 22, Issue 4, April 2000, Pages 259-266
Pediatric Neurology

Substance P immunoreactivity in Rett syndrome

https://doi.org/10.1016/S0887-8994(00)00120-XGet rights and content

Abstract

Severe autonomic dysfunction occurs in Rett syndrome (RS). Substance P, a tachykinin peptide that localizes to several brain regions, including the autonomic nervous system, is reduced in the cerebrospinal fluid of patients with RS. The anatomic localization and intensity of substance P immunoreactivity and glial fibrillary acidic protein-positive astrocytes in the brains of 14 patients with RS were compared with those in the brains of 10 age-matched normal patients. Substance P immunoreactivity expression was significantly decreased in RS tissue compared with control tissue in the following regions: dorsal horns, intermediolateral column of the spinal cord, spinal trigeminal tract, solitary tract and nucleus, parvocellular and pontine reticular nuclei, and locus ceruleus. A less significant decrease of substance P immunoreactivity occurred in the substantia nigra, central gray of the midbrain, frontal cortex, caudate, putamen, globus pallidus, and thalamus. Antiglial fibrillary acidic protein-positive astrocytes were increased in the areas in which substance P immunoreactivity was decreased and in other brain regions. Because many of the brain regions with the greatest decrease in substance P immunoreactivity are involved in the control of the autonomic nervous system, especially the solitary tracts and reticular formation, reduced substance P may contribute to the autonomic dysfunction in RS.

Introduction

Rett syndrome (RS), described by Andreas Rett in 1966 [1], is characterized by a profound mental handicap and motor disability in females. It has a unique clinical phenotype with abnormalities that include dysfunction of the autonomic nervous system, irregularities of respiration and heart rate, altered electrocardiographic findings, increased heart rate variability, constipation, and cool feet [2]. No chemical or morphologic features have been identified specific to RS, but recently, Amir et al. [3] described mutations in the MECP2 gene in seven females with RS. The protein, methyl CpG-binding protein 2, acts as a repressor of transcription, and its role in the pathoetiology of RS is the new focus of research. If MECP2 is not functioning, faulty expression and over transcription of many proteins may occur. The neurotransmitters and their receptors have been scrutinized for abnormalities that could explain the complex and characteristic deficits in RS. Studies of the neurotransmitters have revealed inconsistent alterations (usually decreases) of cerebrospinal fluid (CSF) catecholamines [4], [5], [6], [7] and endorphins [8], elevations of CSF glutamate [9], and decreased choline acetyltransferase activity in the hippocampus, basal ganglia, and thalamus associated with a decreased acetylcholine vesicular transporter protein [10]. CSF serotonin was studied by Campos-Castello et al. [7], and an increase of serotonin receptor binding in the brainstem in three patients with RS has been observed [11]. In 1997, Matsuishi et al.[12] observed that another transmitter, substance P, was decreased in the CSF of patients with RS.

Substance P, a neural peptide belonging to the tachykinin family [13], [14], is widely distributed in the central and peripheral nervous systems. It is considered a neural modulator that alters pain-responsive neurons [15] and neurons concerned with respiratory and cardiovascular functions [16]. Because the CSF levels of substance P are significantly low in patients with RS, we sought to determine its relationship to the autonomic dysfunction that occurs with RS. In this study, we quantified the intensity of substance P immunoreactivity in RS and control brainstem nuclei and other selected brain regions. The numbers of glial fibrillary acidic protein (GFAP)-positive astrocytes in the same regions were also quantified.

Section snippets

Material and methods

The brain tissue of 14 females with RS were examined. The ages of the patients ranged from 6-35 years. The diagnosis of RS had been confirmed by pediatric neurologists, and the studies were coordinated through the Harvard Brain Tissue Resource Center and the International Rett Syndrome Association. The patients had been classified as having stage III (ambulatory) or stage IV (nonambulatory) RS. The RS brains, aside from their decreased weight, revealed no specific neuropathologic findings.

Substance P immunohistochemistry

The conditions for immunohistochemistry were favorable (Fig 1). The postmortem intervals did not appear to affect the intensity of the reaction; that is, the amount of immunoreactivity in the cases with the longest postmortem intervals was similar to that of the cases with shorter intervals. All cases, except one RS case, had a postmortem interval of less than 24 hours, which was the postmortem interval used in the study by Pioro et al. [17]. The substance P immunopositivity was observed, as

Discussion

The results of the present study have confirmed the observation of Matsuishi et al. [12] that substance P is reduced in the CSF of patients with RS. We also quantified substance P immunoreactivity in regions of the brainstem and cerebrum where substance P is normally expressed. Some of the substance P immunoreactive nuclei are involved in the maintenance of body homeostasis-modulating functions, such as cardiorespiratory reflexes, arousal, and peripheral circulation. Thus the role of substance

Acknowledgements

Supported in part by grants from the International Rett Syndrome Association, NIH 2 P30 HD24064-11, and Japan Foundation for Aging Research. Tissue samples were provided by the Harvard Brain Tissue Resource Center, which is supported in part by PHS grant MH/NS 31862.

References (28)

  • H.Y. Zoghbi et al.

    Reduction of biogenic aminic levels in the Rett syndrome

    N Engl J Med

    (1985)
  • H.Y. Zoghbi et al.

    Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome

    Ann Neurol

    (1989)
  • J. Campos-Castello et al.

    Cerebrospinal fluid concentrations of homovanillic acid and 5-hydroxyindoleacetic acid in patients with Rett syndrome

    Pediatrics

    (1991)
  • A. Hamberger et al.

    Elevated CSF glutamate in Rett syndrome

    Neuropediatrics

    (1992)
  • Cited by (0)

    View full text