Oxytocin and autistic disorder: alterations in peptide forms

Abstract

Background: Oxytocin (OT) is synthesized as a prohormone that is sequentially processed to peptides. These peptides are the bioactive amidated form (OT) and the C-terminal extended peptides, OT-Gly, OT-Gly-Lys and OT-Gly-Lys-Arg, which are designated together as OT-X. As an extension of our previous study finding decreased plasma OT in autism, studies were conducted to determine whether there were changes in OT peptide forms in autistic children.

Methods: Twenty eight male subjects (97 ± 20 months; range, 70–139 months), diagnosed with DSM-IV autistic disorder through observation and semi-structured interview, were compared with 31 age-matched nonpsychiatric control subjects (106 ± 22 months; range, 74–140 months). Using OT antisera with different specificity for the peptide forms, we measured plasma OT and OT-X in each group.

Results: T tests showed that there was a decrease in plasma OT (t = 4.4, p < .0001), an increase in OT-X (t = 2.3, p < .03) and an increase in the ratio of OT-X/OT (t = 4.5, p < .0001) in the autistic sample, compared with control subjects.

Conclusions: The results suggest that children with autistic disorder show alterations in the endocrine OT system. Deficits in OT peptide processing in children with autism may be important in the development of this syndrome.

Introduction

Researchers have recently suggested that the social impairments found in autistic disorder are associated with changes in plasma oxytocin (OT) levels (Modahl et al 1998). A central OT system, projecting to limbic and other brain areas, has been implicated in maternal behavior, infant separation distress, sexual behavior, and other general aspects of affiliation in mammals (Insel 1992). Recent studies in an animal model that lack the ability to synthesize the hormone demonstrate changes in behavior, associated with emotionality and aggression Lucot et al 2000, Winslow et al 2000. Based on the idea that social impairments in autism are primary symptoms (Fein et al 1996), it was suggested that this central OT system might be dysfunctional in this population Modahl et al 1993, Waterhouse et al 1996. Our findings that plasma OT is lower in autistic children and has abnormal associations with sociality provide support for a possible role for OT in this disorder. The changes could reflect underlying alterations in the brain OT axis, alterations in peptide receptors, and/or peptide synthesis and processing.

Oxytocin is synthesized in neurons in the hypothalamus as part of a protein precursor, which is enzymatically cleaved and amidated as it is transported axonally (Gainer et al 1987). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT-extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension (Gainer et al 1995). Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994).

Alterations in OT prohormone processing are noted as a normal process of development. Studies in rats and sheep showed that processing of OT-X to OT occurs more completely as the fetus matures Morris et al 1992, Whitnall et al 1985. Whitnall et al (1985) further found, in examining the latency in OT processing compared with its structural relative, vasopressin, that the delay in OT-X conversion corresponded to delays in the appearance of OT in neurites. Altstein and Gainer (1988) determined that OT-X processing in the adult rat was high (over 99% peptide cleavage). In contrast, OT-X processing in the fetus was very low and incomplete, resulting in 40% unprocessed precursor and the accumulation of C-terminally extended nonamidated peptide forms (OT-Gly, OT-Gly-Lys, and OT-Gly-Lys-Arg). Morris and et al (1992) found that plasma levels of OT-X are elevated early in fetal sheep development and then show a decrease as levels of fully processed circulating OT begin to predominate later in gestation. Likewise, OT-X was present in human umbilical arterial and venous blood, with changes associated with labor and delivery (Mueller-Heubach et al 1995). It was suggested that the developmental change in OT processing may contribute to regulation of birth and fetal neural and endocrine development and are attributable to enzymatic activity.

Because our previous study showed that autistic children had lower levels of plasma OT (Modahl et al 1998), it was logical to explore the question as to whether there were alterations in the OT peptide forms.