ORIGINAL ARTICLE Reduced Plasma Apelin Levels in Patients with Autistic Spectrum Disorder Marianna Boso, a,1 Enzo Emanuele, b,1 Pierluigi Politi, a Alessandro Pace, a Mariarosa Arra, b Stefania Ucelli di Nemi, a and Francesco Barale a a Department of Health Sciences, Section of Psychiatry, and b Interdepartment Center for Research in Molecular Medicine (CIRMC), University of Pavia, Pavia, Italy Received for publication June 7, 2006; accepted August 9, 2006 (ARCMED-D-06-00238). Background. Dysregulation of the vasopressin (AVP) system has been implicated in the pathogenesis of autistic spectrum disorder (ASD). Apelin is a recently discovered neuro- peptide that could counteract AVP actions and whose receptors are colocalized with va- sopressin in hypothalamic magnocellular neurons. Aims of the present study were to investigate circulating levels of apelin in patients with ASD and to assess their correlation with plasma AVP concentrations. Methods. Plasma levels of apelin and AVP were measured in a total of 18 patients with ASD and 21 age- and gender-matched healthy comparison subjects. The Childhood Autism Rating Scale (CARS) was used to assess the severity of autistic symptoms. Results. Significantly reduced levels of apelin (p !0.001) and elevated concentrations of AVP (p 5 0.02) were found in ASD patients as compared to controls. Additionally, a sig- nificant inverse correlation between apelin and AVP levels was found within the ASD group (r 5 e0.61; p 5 0.007), but not in healthy participants (r 5 0.26; p 5 0.25). Multivariate linear regression analysis showed that only AVP concentrations indepen- dently predicted apelin values in ASD individuals (b 5 0.42, t 5 2.63, p 5 0.014). No correlation was seen between apelin levels and CARS scores (r 5 0.10; p 5 0.68). Conclusions. Our findings of a significantly reduced peripheral level of apelin coupled with elevated AVP point to a subtle but definite vasopressinergic dysfunction in autism that could play a role in the etiopathophysiology of this disorder in humans. Ó 2007 IMSS. Published by Elsevier Inc. Key Words: Autistic spectrum disorders, Neuropeptides, Vasopressin, Apelin. Introduction In recent years, there has been considerable interest in the possible role played by the vasopressinergic system in the pathogenesis of autistic spectrum disorder (ASD) (1e3). Accordingly, the involvement of vasopressin (AVP) dysre- gulation in autism at an etiopathological level has been ini- tially fostered by numerous studies in animal models showing that mice lacking the vasopressin V1a receptor gene (AVPR1a) have profound behavioral alterations and deficits in social recognition that strictly resemble those of human autism (2,4,5). Although no disease-causing mu- tation in AVPR1a has been detected so far in patients with ASD (6), a very recent study has provided evidence of a sig- nificant association between specific microsatellite poly- morphisms within this gene and autism (7). Of interest, preliminary data seem also to indicate that children with ASD could display significantly increased levels of AVP in their plasma (8). Since AVP has been shown to enhance and facilitate a number of social behav- iors (9,10), it was hypothesized that autism could represent a ‘‘vasopressin-resistance’’ condition, characterized by a general hyporesponsiveness of AVPR1a receptors to the prosocial effects of AVP (11). The recently discovered neuropeptide apelin has been sug- gested to play a critical role in the central regulation of the vasopressinergic system (12,13). Apelin is a 13-aminoacid 1 These authors contributed equally to this work. Address reprint requests to: Dr. Enzo Emanuele, Interdepartment Center for Research in Molecular Medicine (CIRMC), University of Pavia, Viale Taramelli, 24, I-27100 Pavia, Italy; E-mail: ccirmc@unipv.it 0188-4409/06 $esee front matter. Copyright Ó 2007 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2006.08.003 Archives of Medical Research 38 (2007) 70e74