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Dysfunctional dopaminergic neurotransmission in asocial BTBR mice.

Squillace M, Dodero L, Federici M, Migliarini S, Errico F, Napolitano F, Krashia P, Di Maio A, Galbusera A, Bifone A, Scattoni ML, Pasqualetti M, Mercuri NB, Usiello A, Gozzi A - Transl Psychiatry (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Ceinge Biotecnologie Avanzate, Naples, 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.

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Blunted GBR 12909-induced motor activity in BTBR mice. Motor activity induced by 10 mg kg−1 and (a, b) and 20 mg kg−1 (c, d) GBR 12909 in B6 (10 mg kg−1, n=5; 20 mg kg−1, n=6) and BTBR mice (n=6 per dose). Two independent vehicle-treated groups were used to test the effect of 10 mg kg−1 (n=6 per strain) and 20 mg kg−1 GBR 12909 (C57BL/6J, n=5; BTBR, n=6). Locomotion was expressed as distance travelled, measured every 10 min over a 30-min session and presented as time course (a, c) or total activity (b, d). All values are expressed as mean±s.e.m. *P<0.05, compared with vehicle-treated group within strain (one-way analysis of variance).
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fig2: Blunted GBR 12909-induced motor activity in BTBR mice. Motor activity induced by 10 mg kg−1 and (a, b) and 20 mg kg−1 (c, d) GBR 12909 in B6 (10 mg kg−1, n=5; 20 mg kg−1, n=6) and BTBR mice (n=6 per dose). Two independent vehicle-treated groups were used to test the effect of 10 mg kg−1 (n=6 per strain) and 20 mg kg−1 GBR 12909 (C57BL/6J, n=5; BTBR, n=6). Locomotion was expressed as distance travelled, measured every 10 min over a 30-min session and presented as time course (a, c) or total activity (b, d). All values are expressed as mean±s.e.m. *P<0.05, compared with vehicle-treated group within strain (one-way analysis of variance).

Mentions: To assess the behavioural relevance of the alterations found with fMRI, we evaluated the stimulant in vivo effect of GBR 12909 on the horizontal motor activity of BTBR and B6 mice, a behaviour dependent on DA neurotransmission in the nucleus accumbens.46,47 Consistent with the imaging results, both the GBR 12909 doses tested (10 and 20 mg kg−1 i.p.) produced robust and sustained horizontal motor responses in B6 mice, but failed to elicit significant forward locomotor activity in BTBR mice (Figure 2a; two-way ANOVA with repeated measures, treatment effect: 10 mg kg−1, B6: F(1,18)=7.222, P=0.0249; BTBR: F(1,20)=0.482, P=0.5031; Figure 2c; 20 mg kg−1, B6: F(1,18)=9.313, P=0.0138; BTBR: F(1,20)=4.892, P=0.0514). Analogous results were obtained when the effect was expressed as cumulative motor activity over the experimental time-window examined (0–30 min; Figure 2b, one-way ANOVA, 10 mg kg−1: B6 F(1,9)=7.222, P=0.0249; BTBR, F(1,10)=0.482, P=0.5031; Figure 2d, 20 mg kg−1: B6, F(1,9)=9.313, P=0.0138; BTBR: F(1,10)=4.892, P=0.0514). Together with the fMRI findings, these behavioural data corroborate the presence of a severe striatal DA hypo-responsiveness in BTBR mice.


Dysfunctional dopaminergic neurotransmission in asocial BTBR mice.

Squillace M, Dodero L, Federici M, Migliarini S, Errico F, Napolitano F, Krashia P, Di Maio A, Galbusera A, Bifone A, Scattoni ML, Pasqualetti M, Mercuri NB, Usiello A, Gozzi A - Transl Psychiatry (2014)

Blunted GBR 12909-induced motor activity in BTBR mice. Motor activity induced by 10 mg kg−1 and (a, b) and 20 mg kg−1 (c, d) GBR 12909 in B6 (10 mg kg−1, n=5; 20 mg kg−1, n=6) and BTBR mice (n=6 per dose). Two independent vehicle-treated groups were used to test the effect of 10 mg kg−1 (n=6 per strain) and 20 mg kg−1 GBR 12909 (C57BL/6J, n=5; BTBR, n=6). Locomotion was expressed as distance travelled, measured every 10 min over a 30-min session and presented as time course (a, c) or total activity (b, d). All values are expressed as mean±s.e.m. *P<0.05, compared with vehicle-treated group within strain (one-way analysis of variance).
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Related In: Results  -  Collection

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Show All Figures
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fig2: Blunted GBR 12909-induced motor activity in BTBR mice. Motor activity induced by 10 mg kg−1 and (a, b) and 20 mg kg−1 (c, d) GBR 12909 in B6 (10 mg kg−1, n=5; 20 mg kg−1, n=6) and BTBR mice (n=6 per dose). Two independent vehicle-treated groups were used to test the effect of 10 mg kg−1 (n=6 per strain) and 20 mg kg−1 GBR 12909 (C57BL/6J, n=5; BTBR, n=6). Locomotion was expressed as distance travelled, measured every 10 min over a 30-min session and presented as time course (a, c) or total activity (b, d). All values are expressed as mean±s.e.m. *P<0.05, compared with vehicle-treated group within strain (one-way analysis of variance).
Mentions: To assess the behavioural relevance of the alterations found with fMRI, we evaluated the stimulant in vivo effect of GBR 12909 on the horizontal motor activity of BTBR and B6 mice, a behaviour dependent on DA neurotransmission in the nucleus accumbens.46,47 Consistent with the imaging results, both the GBR 12909 doses tested (10 and 20 mg kg−1 i.p.) produced robust and sustained horizontal motor responses in B6 mice, but failed to elicit significant forward locomotor activity in BTBR mice (Figure 2a; two-way ANOVA with repeated measures, treatment effect: 10 mg kg−1, B6: F(1,18)=7.222, P=0.0249; BTBR: F(1,20)=0.482, P=0.5031; Figure 2c; 20 mg kg−1, B6: F(1,18)=9.313, P=0.0138; BTBR: F(1,20)=4.892, P=0.0514). Analogous results were obtained when the effect was expressed as cumulative motor activity over the experimental time-window examined (0–30 min; Figure 2b, one-way ANOVA, 10 mg kg−1: B6 F(1,9)=7.222, P=0.0249; BTBR, F(1,10)=0.482, P=0.5031; Figure 2d, 20 mg kg−1: B6, F(1,9)=9.313, P=0.0138; BTBR: F(1,10)=4.892, P=0.0514). Together with the fMRI findings, these behavioural data corroborate the presence of a severe striatal DA hypo-responsiveness in BTBR mice.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Ceinge Biotecnologie Avanzate, Naples, 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.

Show MeSH
Related in: MedlinePlus