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Transl Psychiatry. 2014 Aug 19;4:e427. doi: 10.1038/tp.2014.69.

Dysfunctional dopaminergic neurotransmission in asocial BTBR mice.

Author information

1
Ceinge Biotecnologie Avanzate, Naples, Italy.
2
1] Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy [2] Istituto Italiano di Tecnologia, Pavis, Genoa, Italy.
3
1] Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy [2] Laboratorio di Neurologia Sperimentale, IRCCS Fondazione Santa Lucia, Rome, Italy.
4
Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa, Italy.
5
1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy.
6
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
7
Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
8
Neurotoxicology and Neuroendocrinology Section, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
9
1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples (SUN), Caserta, Italy.

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.

PMID:
25136890
PMCID:
PMC4150243
DOI:
10.1038/tp.2014.69
[Indexed for MEDLINE]
Free PMC Article

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