CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Oxytocin and vasopressin in autism spectrum disorders

Despite intensive research using a variety of techniques, the pathophysiology of autism spectrum disorders (ASD) remains largely unknown. Several lines of evidence indicate that genetic factors are important in autism susceptibility, but common genetic variants have proven very difficult to identify and autism genetic susceptibility is nowadays believed to result from the combined action of several common genetic variants. Recent findings suggest that in ASD common developmental pathways may be disrupted at multiple points and that multiple disruption may be needed to results in the full clinical manifestation of autism. Furthermore, several factors suggest that early intervention may be valuable even if they do not address autism's etiology; these factors include the redundancy of neuro-developmental processes, their sensitivity to regulation by a variety of environmental and endogenous factors and the evidence of cortical plasticity in compensation for early developmental alterations. Pharmacological intervention provided to young children with autism may be successful if it targets the regulation of early neurodevelopmental processes and it increases opportunities for plasticity. A potential target of such pharmacological intervention is represented by the oxytocin/vasopressin system. OT and AVP are two neuropeptides that play crucial roles in reproductive, social and adaptive behaviours. Among their firmly established roles in mammals, there is the ability of OT and AVP to make individuals to remember previously met individuals, i.e. a form of social recognition that is essential to establish all complex relationships. Interestingly, in knockout mice models for OT/AVP receptors, a impairment in social recognition has been observed confirming that the OT/AVP system is crucially involved in the processing of socially relevant cues. Thus, the OT/AVP system may represent a common endopoint at which several genetic alterations converge to produce the disturbance of social behaviour that is the hallmark of ASD. Pilot clinical trials have indeed shown positive effects of OT in treating autistic patients. In particular, OT administration has been shown to reduce the repetitive behaviours and to increase the retention of social cognition in adults with autistic and Asperger's disorders, suggesting that OT facilitates social information processing in autistic patients.

Our research program is aimed at validating the use of OT/AVP compounds to treat the core symptoms of ASD.


1. Synthesis and pharmacological characterization of new OT/AVP peptides

Even if OT has been recently reported to improve cognitive deficits in autistic patients, its clinical use is hampered by several factors: (i) OT has a short half-life, of about 6 minutes; (ii) OT, at high concentrations, also binds to and activates the vasopressin V1A and V1B receptors, that are highly expressed in the brain; (iii) OT acts on the oxytocin receptor (OTR) to promote the receptor coupling to different G proteins, with the consequent activation of multiple signaling pathways (Reversi et al., 2005). The rationale and the experimental plan for the development of new selective and more potent OT analogues such a functional selective and bivalent compounds is described in line A3.


2. In vivo evaluation of OT/AVP peptides to revert autism-like behavioural in mice models of ASD

Our preliminary experiments confirmed that knockout OTR-/- mice display some behavioural alterations resembling those of autism, as they resulted to be impaired in social recognition as well as in social memory. As we have found that these abnormal features could be reversed by acute icv somministration of OT/AVP analogs, these animals represent a good model for the screening of new OT/AVP compounds of potential use in ASD.


3. Eeffects of OT/AVP compounds on neuronal and glial cell proliferation migration, differentiation and on the development of appropriate synaptic networks

The capability of OT/AVP peptides to regulate neuronal plasticity and connectivity and to compensate neurodevelopmental alterations will be analyzed in OTR+/- and OTR-/- mice.

With this work, we hope to clarify whether the OT/AVP system modulates synaptic plasticity and neuronal connectivity, as well as to provide the rationale for the use of new drugs for the therapy of autism.

Publications

  • Chini B, Manning M, Guillon G (2008) Affinity and efficacy of selective agonists and antagonists for vasopressin and oxytocin receptors: an "easy guide" to receptor pharmacology. Prog. Brain Res. 170:513-7.
  • Manning M, Stoev S, Chini B, Durroux T, Mouillac B, Guillon G (2008) Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. Prog. Brain Res. 170:473-512.
  • Chini B, Manning M (2007) Agonist selectivity in the oxytocin/vasopressin receptor family: new insights and challenges. Biochem. Soc. Trans. 35:737-41.
  • Reversi A, Rimoldi V, Marrocco T, Cassoni P, Bussolati G, Parenti M, Chini B (2005) The oxytocin receptor antagonist atosiban inhibits cell growth via a "biased agonist" mechanism. J. Biol. Chem. 280:16311-8.

Grants

Fondazione Cariplo, Milano

Collaborations

This project will be carried out in close collaboration with:

  • M. Parenti, (University of Milano-Bicocca), who will provide neurobiological and cell biology expertise.
  • M.E. Sala, (University of Milano), who has developed a longer than 20-year experience in animal neuro-behavioural testing.
  • M. Toselli, (Univ. Pavia), who will provide electrophysiological expertise.
  • M. Manning, (University of Toledo, Ohio, USA), the world-wide recognized leader in the synthesis of OT/AVP peptides.

 

PI photo

Bice Chini

Contact information

email  E-mail

email  +39 02 5031 6958

Participating staff
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