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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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Preserved Drd1-mediated motor stimulation and signalling in BTBR mice. Representative images of coronal sections showing Drd1 mRNA expression in the striatum of B6 (a) and BTBR (b) animals (scale bar, 1.5 mm). (c) Histogram showing Drd1 mRNA levels in BTBR animals (n=7) obtained after densitometric quantification of autoradiograms expressed as percentage variation as compared with B6 control animals (n=4). (d) Motor activity induced by 1.25 and 2.5 mg kg−1 SKF 81297 in B6 (vehicle, n=6; 1.25 mg kg−1, n=7; 2.5 mg kg−1, n=6) and BTBR animals (vehicle, n=5; 1.25 mg kg−1, n=6; 2.5 mg kg−1, n=6). Locomotion is expressed as the total distance travelled (in cm). *P<0.05, **P<0.01, compared with vehicle-treated group within strain (Fisher's post hoc analysis). P-Ser845-GluR1 protein levels determined by western blotting in the striatum of B6 (e) and BTBR mice (f) treated with 5 mg kg−1 SKF 81297 (B6, n=8; BTBR, n=3) or vehicle (B6, n=9; BTBR, n=3). The top panels in e and f show representative blots comparing the different strains. *P<0.05, **P<0.01, compared with vehicle, Student's t-test (f and e, respectively). All values are expressed as mean±s.e.m.
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fig3: Preserved Drd1-mediated motor stimulation and signalling in BTBR mice. Representative images of coronal sections showing Drd1 mRNA expression in the striatum of B6 (a) and BTBR (b) animals (scale bar, 1.5 mm). (c) Histogram showing Drd1 mRNA levels in BTBR animals (n=7) obtained after densitometric quantification of autoradiograms expressed as percentage variation as compared with B6 control animals (n=4). (d) Motor activity induced by 1.25 and 2.5 mg kg−1 SKF 81297 in B6 (vehicle, n=6; 1.25 mg kg−1, n=7; 2.5 mg kg−1, n=6) and BTBR animals (vehicle, n=5; 1.25 mg kg−1, n=6; 2.5 mg kg−1, n=6). Locomotion is expressed as the total distance travelled (in cm). *P<0.05, **P<0.01, compared with vehicle-treated group within strain (Fisher's post hoc analysis). P-Ser845-GluR1 protein levels determined by western blotting in the striatum of B6 (e) and BTBR mice (f) treated with 5 mg kg−1 SKF 81297 (B6, n=8; BTBR, n=3) or vehicle (B6, n=9; BTBR, n=3). The top panels in e and f show representative blots comparing the different strains. *P<0.05, **P<0.01, compared with vehicle, Student's t-test (f and e, respectively). All values are expressed as mean±s.e.m.

Mentions: The DA D1 receptor (Drd1) is among the most important postsynaptic effectors of DA function.48Drd1 mRNA expression levels were measured in the striatum of BTBR and B6 mice using in situ hybridization with a 35S-radiolabelled antisense riboprobe. Densitometric analyses revealed comparable levels of Drd1 in BTBR and B6 mice (P=0.51, Student's t-test; Figure 3a, b and c). The functional reactivity of Drd1 in both strains was next probed in vivo, by measuring motor activity elicited by selective agonist SKF 81297 administration (1.25 and 2.5 mg kg−1), as previously reported49 (Figure 3d). A comparable dose-dependent increase in locomotor activity was observed in both strains (one-way ANOVA: B6, F(2,14)=5.148, P=0.0211; BTBR, F(2,16)=10.341, P=0.0013), corroborating the presence of a functionally reactive Drd1 receptor pool 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)

Preserved Drd1-mediated motor stimulation and signalling in BTBR mice. Representative images of coronal sections showing Drd1 mRNA expression in the striatum of B6 (a) and BTBR (b) animals (scale bar, 1.5 mm). (c) Histogram showing Drd1 mRNA levels in BTBR animals (n=7) obtained after densitometric quantification of autoradiograms expressed as percentage variation as compared with B6 control animals (n=4). (d) Motor activity induced by 1.25 and 2.5 mg kg−1 SKF 81297 in B6 (vehicle, n=6; 1.25 mg kg−1, n=7; 2.5 mg kg−1, n=6) and BTBR animals (vehicle, n=5; 1.25 mg kg−1, n=6; 2.5 mg kg−1, n=6). Locomotion is expressed as the total distance travelled (in cm). *P<0.05, **P<0.01, compared with vehicle-treated group within strain (Fisher's post hoc analysis). P-Ser845-GluR1 protein levels determined by western blotting in the striatum of B6 (e) and BTBR mice (f) treated with 5 mg kg−1 SKF 81297 (B6, n=8; BTBR, n=3) or vehicle (B6, n=9; BTBR, n=3). The top panels in e and f show representative blots comparing the different strains. *P<0.05, **P<0.01, compared with vehicle, Student's t-test (f and e, respectively). All values are expressed as mean±s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: Preserved Drd1-mediated motor stimulation and signalling in BTBR mice. Representative images of coronal sections showing Drd1 mRNA expression in the striatum of B6 (a) and BTBR (b) animals (scale bar, 1.5 mm). (c) Histogram showing Drd1 mRNA levels in BTBR animals (n=7) obtained after densitometric quantification of autoradiograms expressed as percentage variation as compared with B6 control animals (n=4). (d) Motor activity induced by 1.25 and 2.5 mg kg−1 SKF 81297 in B6 (vehicle, n=6; 1.25 mg kg−1, n=7; 2.5 mg kg−1, n=6) and BTBR animals (vehicle, n=5; 1.25 mg kg−1, n=6; 2.5 mg kg−1, n=6). Locomotion is expressed as the total distance travelled (in cm). *P<0.05, **P<0.01, compared with vehicle-treated group within strain (Fisher's post hoc analysis). P-Ser845-GluR1 protein levels determined by western blotting in the striatum of B6 (e) and BTBR mice (f) treated with 5 mg kg−1 SKF 81297 (B6, n=8; BTBR, n=3) or vehicle (B6, n=9; BTBR, n=3). The top panels in e and f show representative blots comparing the different strains. *P<0.05, **P<0.01, compared with vehicle, Student's t-test (f and e, respectively). All values are expressed as mean±s.e.m.
Mentions: The DA D1 receptor (Drd1) is among the most important postsynaptic effectors of DA function.48Drd1 mRNA expression levels were measured in the striatum of BTBR and B6 mice using in situ hybridization with a 35S-radiolabelled antisense riboprobe. Densitometric analyses revealed comparable levels of Drd1 in BTBR and B6 mice (P=0.51, Student's t-test; Figure 3a, b and c). The functional reactivity of Drd1 in both strains was next probed in vivo, by measuring motor activity elicited by selective agonist SKF 81297 administration (1.25 and 2.5 mg kg−1), as previously reported49 (Figure 3d). A comparable dose-dependent increase in locomotor activity was observed in both strains (one-way ANOVA: B6, F(2,14)=5.148, P=0.0211; BTBR, F(2,16)=10.341, P=0.0013), corroborating the presence of a functionally reactive Drd1 receptor pool 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