title: Dysfunctional dopaminergic neurotransmission in asocial BTBR mice.
abstract: Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by pronounced social and communication deficits and stereotyped behaviours. Recent psychosocial and neuroimaging studies have highlighted reward-processing deficits and reduced dopamine (DA) mesolimbic circuit reactivity in ASD patients. However, the neurobiological and molecular determinants of these deficits remain undetermined. Mouse models recapitulating ASD-like phenotypes could help generate hypotheses about the origin and neurophysiological underpinnings of clinically relevant traits. Here we used functional magnetic resonance imaging (fMRI), behavioural and molecular readouts to probe dopamine neurotransmission responsivity in BTBR T(+) Itpr3(tf)/J mice (BTBR), an inbred mouse line widely used to model ASD-like symptoms owing to its robust social and communication deficits, and high level of repetitive stereotyped behaviours. C57BL/6J (B6) mice were used as normosocial reference comparators. DA reuptake inhibition with GBR 12909 produced significant striatal DA release in both strains, but failed to elicit fMRI activation in widespread forebrain areas of BTBR mice, including mesolimbic reward and striatal terminals. In addition, BTBR mice exhibited no appreciable motor responses to GBR 12909. DA D1 receptor-dependent behavioural and signalling responses were found to be unaltered in BTBR mice, whereas dramatic reductions in pre- and postsynaptic DA D2 and adenosine A2A receptor function was observed in these animals. Overall these results document profoundly compromised DA D2-mediated neurotransmission in BTBR mice, a finding that is likely to have a role in the distinctive social and behavioural deficits exhibited by these mice. Our results call for a deeper investigation of the role of dopaminergic dysfunction in mouse lines exhibiting ASD-like phenotypes, and possibly in ASD patient populations.
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Squillace
authors.affiliation: 1] Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy [2] Istituto Italiano di Tecnologia, Pavis, Genoa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Dodero
authors.affiliation: 1] Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy [2] Laboratorio di Neurologia Sperimentale, IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Federici
authors.affiliation: Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Migliarini
authors.affiliation: 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Errico
authors.affiliation: 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Napolitano
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Krashia
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Di Maio
authors.affiliation: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Galbusera
authors.affiliation: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bifone
authors.affiliation: Neurotoxicology and Neuroendocrinology Section, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: M L
authors.initials: ML
authors.lastname: Scattoni
authors.affiliation: Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pasqualetti
authors.affiliation: 1] Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy [2] Laboratorio di Neurologia Sperimentale, IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: N B
authors.initials: NB
authors.lastname: Mercuri
authors.affiliation: 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples (SUN), Caserta, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Usiello
authors.affiliation: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gozzi
mesh_terms: D000818:Animals; D001143:Arousal / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis / Q000503:physiopathology* / Q000523:psychology; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D008032:Limbic System / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008636:Mesencephalon / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009415:Nerve Net / Q000503:physiopathology; D017448:Receptors, Dopamine D2 / Q000502:physiology; D012016:Reference Values; D012919:Social Behavior; D013239:Stereotyped Behavior; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D017448:Receptors, Dopamine D2; D004298:Dopamine