What may be the anatomical basis that secretin can improve the mental functions in autism?

doi:10.1016/S0167-0115(02)00200-8

Regulatory Peptides

Volume 109, Issues 1–3, 15 November 2002, Pages 167-172

https://doi.org/10.1016/S0167-0115(02)00200-8 Get rights and content

Abstract

Autism was first described and characterized as a behavioral disorder more than 50 years ago. The major abnormality in the central nervous system is a cerebellar atrophy. The characteristic histological sign is a striking loss or abnormal development in the Purkinje cell count. Abnormalities were also found in the limbic system, in the parietal and frontal cortex, and in the brain stem. The relation between secretin and autism was observed 3 years ago. Clinical observations by Horváth et al. [J. Assoc. Acad. Minor. Physicians 9 (1998) 9] supposed a defect in the role of secretin and its receptors in autism. The aim of the present work was to study the precise localization of secretin immunoreactivity in the nervous system using an immunohistochemical approach. No secretin immunoreactivity was observed in the forebrain structures. In the brain stem, secretin immunoreactivity was observed in the mesencephalic nucleus of the trigeminal nerve, in the superior olivary nucleus, and in scattered cells of the reticular formation. The most intensive secretin immunoreactivity was observed in the Purkinje cells of the whole cerebellum and in some of the neurons of the central cerebellar nuclei. Secretin immunoreactivity was also observed in a subpopulation of neurons in the primary sensory ganglia. This work is the first immunohistochemical demonstration of secretin-immunoreactive elements in the brain stem and in primary sensory ganglia.

Introduction

Autism was first described in 1943 by Kanner [1]. It was characterized as a behavioral disorder. In the last two decades, neuropathological abnormalities were described in various brain regions of autistic patients. Most frequently and consistently, the abnormalities were found in the cerebellum. Ritvo et al. [2] observed a lower total Purkinje cell count in autistic subjects than in healthy ones. Bauman [3] has described atrophy of inferolateral parts of the cerebellar hemispheres. The characteristic sign was a striking loss of Purkinje cells and, to a lesser extent, of granule cells. The low number of Purkinje cells may be due to an abnormal developmental sequence of these cells. Several authors have described abnormalities in the brain stem. The olivary neurons were smaller and pale [3], while others have demonstrated abnormally larger size of parietal cortex in autistic subjects than in healthy one [4]. In the forebrain, abnormalities were also present in various part of the limbic system. A direct pathway between the fastigial nucleus of the cerebellum and the septal nuclei and the amygdala suggests a role of the cerebellum in emotional reactions, behavior, and learning [5].

The present understanding of the neurochemical basis of autism is limited. There is a very intensive search for those factors which, or the most of which are responsible for the autistic phenomenon. The relation of autism and the neurotransmitters is intensively studied. Several drugs were found to improve the mental functions in autism. One of these molecules is the dopamin, so-called “pleasure molecule”. Positron emission tomography (PET) suggests abnormalities of dopaminergic and serotoninergic function in autism (see review [6]). Hyperserotoninemia and hyper-β-endorphinemia was also observed in autistic children [7].

There is a two-decade trial to find relation between neuropeptides and autism. Several neuropeptides were used to blunt the autistic phenomenon such as ORG2766 (ACTH analogue) [8], MSH [9], vasopressin, and oxytocin [10].

At this moment, no single therapeutic agent or combination thereof is appropriate for the treatment of autism. Recently, it was described by one of the authors [11], [12] that in autistic children, who exhibited gastrointestinal symptoms, intravenous (iv) administration of secretin resulted in about fivefold higher pancreatobiliary fluid secretion than in healthy children. The parents of these children reported better mental functions after the test (improved eye contact, alertness, expansion of expressive language). However, there are several controversial results. According to Sandler et al. [13] and Dunn-Geier et al. [14], a single infusion of secretin is not an effective treatment of autism.

Secretin was discovered a century ago by Bayliss and Starling [15] who reported that a blood-born substance is responsible for the enhanced pancreatic fluid secretion in response to duodenal stimulation. They introduced the term of “hormone”. Secretin was characterized 60 years later [16]. It is composed of 27 amino acids. Secretin is present in entero-endocrine S cells of the upper part of the gastrointestinal tract and in the Langerhans' islets (for review, see Ref. [17]). The presence of secretin in endocrine organs was also demonstrated. It was observed in both anterior and posterior pituitaries, in the pineal gland [18], [19], and in several regions of the central nervous system, among them, in the cerebellum using RIA [18]. The expression of the precursor gene was also demonstrated in the medulla, pons, and pituitary [20]. The precise localization of secretin immunoreactivity was not described at that time.

The aim of the present experiment was to systematically map the distribution of secretin-immunoreactive neuronal elements in the central nervous system using an immunohistochemical approach.

Section snippets

Materials and methods

Adult Sprague–Dawley male rats (300–350 g) were used for the experiments. They were kept in a light- and temperature-controlled vivarium (14–10 h light–dark cycle, and 22±2 °C). They were fed with standard lab chow and water ad libitum.

Five rats received colchicine (200 μg/20 μl) intracerebroventricularly (i.c.v.) into the lateral ventricle using a stereotactic approach. The parameters of the i.c.v. injection were the following: 7.2 mm anterior to the ear bar, 1.5 mm lateral from the midline,

Results

In colchicine-treated rats, secretin-immunoreactive cells, and fibers were seen in several structures of the central nervous system; however, in intact rats, we were not able to observe secretin-immunoreactive elements.

Discussion

In colchicine-treated rats secretin accumulated in neurons, and its amount was enough for immunostaining; however, in intact rats, we were not able to stain secretin either in the brain or in the sensory ganglia. In rat under normal physiological conditions, the level of secretin seems to be below the limit of the sensitivity of our immunostaining method.

The distribution of the secretin immunoreactivity has shown a unique and characteristic pattern: it was observed in the cerebellum, in primary

Acknowledgements

We are grateful to Mrs. Anna Takács for her technical assistance and to Beata Urák for the computer assistance. This work was supported by OTKA grant T034429 for KK and MK.

References (24)

R.G. Heath et al.
Ascending projections of the cerebellar fastigial nucleus to the hippocampus, amygdala, and other temporal lobe sites ewoked potential and histological studies in monkeys and cats
Exp. Neurol.
(1974)
M. Leboyer et al.
Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relivates
Biol. Psychiatry
(1999)
J.K. Buitelaar et al.
The adrenocorticotropic hormone (4–9) analog ORG 2766 benefits autistic children: report on a second controlled clinical trial
J. Am. Acad. Child Adolesc. Psych.
(1992)
K. Horváth et al.
Gastrointestinal abnormalities in children with autistic disorder
J. Pediatr.
(1999)
J.E. Jorpes et al.
Amino acid composition and en-terminal amino acid sequence of porcine secretin
BBRC
(1962)
C.G. Charlton et al.
Secretin immunoreactivity in rat and pig brain
Peptides
(1981)
C.G. Charlton et al.
Secretin in the rat hypothalamo–pituitary system: localization, identification and characterization
Peptides
(1982)
N. Itoh et al.
The secretin precursor gene. Structure of the coding region and expression in the brain
J. Biol. Chem.
(1991)
L. Kanner
Autistic disturbance of affective contact
Nerv. Child
(1943)
E.R. Ritvo et al.
Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC autopsy research report
Am. J. Psychiatry
(1986)

M.L. Bauman

Microscopic neuroanatomic abnormalities in autism

Pediatrics

(1991)

E. Courchesne et al.

Parietal lobe abnormalities detected with MR in patients with infantile autism

AJR

(1993)

Cited by (34)

Fantastic voyage: Chasing oxytocin from the bedside to the bench and back again
2024, Comprehensive Psychoneuroendocrinology
This is the story of my 50-year career in medicine and research, and the people who influenced and helped me most along the way. I recount the way in which I became interested in oxytocin early in my career as a child psychiatrist, and how it led me back to Columbia University, my alma mater, to study oxytocin's role in mother-child innate behaviors. I recount how oxytocin/oxytocin receptor signaling was central to my basic and clinical research and present a new theory on mother-infant emotional behaviors that challenges 400 years of brain-centric science. My history underscores the important and unique perspective women bring to science and why women are especially needed in the sciences. I hope to inspire young women (and young men) who are beginning their careers in research.
Signaling mechanisms of secretin receptor
2006, Regulatory Peptides
Secretin, a 27-amino acid gastrointestinal peptide, was initially discovered based on its activities in stimulating pancreatic juice. In the past 20 years, secretin was demonstrated to exhibit pleiotropic functions in many different tissues and more importantly, its role as a neuropeptide was substantiated. To carry out its activities in the central nervous system and in peripheral organs, secretin interacts specifically with one known receptor. Secretin receptor, a member of guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) in the secretin/VIP/glucagon subfamily, possesses the characteristics of GPCR with seven conserved transmembrane domains, a relatively large amino-terminal extracellular domain and an intracellular carboxyl terminus. The structural features and signal transduction pathways of the secretin receptor in various tissues are reviewed in this article.
Partial reversal of phencyclidine-induced impairment of prepulse inhibition by secretin
2005, Biological Psychiatry
Secretin is a “gut-brain” peptide whose neural function is as yet poorly understood. Several clinical studies have reported modestly increased social interaction in autistic children following intravenous secretin administration. Very recently secretin also was administered to schizophrenic patients and found to increase social interaction in some individuals.
In light of this finding, we assessed the ability of secretin to reverse phencyclidine- (PCP) induced impairment in prepulse inhibition (PPI), a leading animal model of sensorimotor gating deficits in schizophrenia.
Similar to atypical antipsychotics, secretin (1, 3, 10, 30, and 100 μg/kg) partially and dose-dependently reversed the PCP-induced deficit in PPI without significantly affecting baseline startle when administered intraperitoneally (IP) 10 minutes following IP administration of PCP (3 mg/kg).
This finding may be relevant to observations of antipsychotic efficacy of secretin in schizophrenic patients as well as our previous report that systemically administered secretin is capable of modulating conditioned fear, even at quite low doses.
Secretin, a known gastrointestinal peptide, is widely expressed during mouse embryonic development
2005, Gene Expression Patterns
The gastrointestinal functions of the 27-amino acid secretin peptide have been well established. In previous prenatal studies, secretin expression in the rat duodenum was reported after day 17 of gestation while its expression in other organs and its functions in the developing embryos are still unknown. By in situ hybridization and immunohistochemical staining, secretin transcripts and peptides were found to be widely expressed in mouse embryos. Consistent with the idea that secretin is a brain-gut peptide, its expressions are present in several developing brain regions such as cephalic mesenchyme, cerebellar primordium and choroid plexus as well as the epithelial villi lining and inner circular muscle of the developing intestine. Other than these organs, secretin was also detected in the developing heart including the ventricular epicardium and myocardium and certain structures of the developing kidney like ureteric bud, collecting duct and glomerulus. These observations strongly suggest for a functional role of secretin during mouse embryonic development.
Predicted role of secretin and oxytocin in the treatment of behavioral and developmental disorders: implications for autism
2005, International Review of Neurobiology
Citation Excerpt :
Cerebellar vermal connections with the hippocampal formation, amygdala, and hypothalamus form an integrated network implicated in adverse conditioning of fear responses (Sacchetti et al., 2005). Immunohistochemical techniques used to localize secretin have shown the highest immunoreactivity in the Purkinje cells of the cerebellum (Koves et al., 2002). Reduced numbers and volume of Purkinje cells have been reported in the cerebellum of autistic patients (Bailey et al., 1998; Bauman and Kemper, 2005).
This chapter reviews evidence that two neuropeptides—secretin and oxytocin—are critical in the conditioning of infant adaptive behavioral patterns and that peptidergic mechanisms are abnormal in developmental disorders, such as autism. The clinical observations in the treatment of autism justify the role of peptides in the neurological manifestations of visceral diseases encompassing emotional/visceral brain regions abnormal in autism. The studies have thus demonstrated that (1) visceral inflammation activates visceral/emotional brain regions in areas known to be abnormal in autism, (2) secretin, like oxytocin, activates many of the same visceral/emotional brain regions that are dysregulated in chronic cerebral and visceral disorders, such as autism, (3) a structural basis for the mechanisms of action of secretin and oxytocin was clarified (4) secretin as well as oxytocin is synthesized in the hypothalamus and may act on structures involved in the pathophysiology of autism (5) secretin and oxytocin localize to perivascular and subependymal regions of the paraventricular hypothalamus, suggesting a chemosensory and secretory function.
Secretin and autism: A basic morphological study about the distribution of secretin in the nervous system
2004, Regulatory Peptides
For the first time, the relationship between secretin and autism has been demonstrated by one of us. Intravenous administration of secretin in autistic children caused a fivefold higher pancreaticobiliary fluid secretion than in healthy ones and, at least in some of the patients, better mental functions were reported after the secretin test. Because the precise localization of secretin in the brain is still not completely known, the abovementioned observation led us to map secretin immunoreactivity in the nervous system of several mammalian species. In the present work, the distribution of secretin immunoreactivity in cat and human nervous systems was compared with that of rats using an immunohistochemical approach. Secretin immunoreactivity was observed in the following brain structures of both humans and in colchicine-treated rats: (1) Purkinje cells in the cerebellar cortex; (2) central cerebellar nuclei; (3) pyramidal cells in the motor cortex; and (4) primary sensory neurons. Additionally, secretin immnoreactive cells were observed in the human hippocampus and amygdala and in third-order sensory neurons of the rat auditory system. In cats, secretin was only observed in the spinal ganglia. Our findings support the view that secretin is not only a gastrointestinal peptide but that it is also a neuropeptide. Its presence or the lack of its presence may have a role in the development of behavioral disorders.

View all citing articles on Scopus

View full text

What may be the anatomical basis that secretin can improve the mental functions in autism?

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Exp. Neurol.

Biol. Psychiatry

J. Am. Acad. Child Adolesc. Psych.

J. Pediatr.

BBRC

Peptides

Peptides

J. Biol. Chem.

Autistic disturbance of affective contact

Nerv. Child

Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC autopsy research report

Am. J. Psychiatry

Microscopic neuroanatomic abnormalities in autism

Pediatrics

Parietal lobe abnormalities detected with MR in patients with infantile autism

AJR