Altered dopaminergic firing pattern and novelty response underlie ADHD-like behavior of SorCS2-deficient mice

Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic paradoxical response to drugs affecting the dopaminergic system. H...

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Bibliographic Details
Published in:	Translational psychiatry 2021-01, Vol.11 (1), p.74-74, Article 74
Main Authors:	Olsen, Ditte, Wellner, Niels, Kaas, Mathias, de Jong, Inge E M, Sotty, Florence, Didriksen, Michael, Glerup, Simon, Nykjaer, Anders
Format:	Article
Language:	eng
Subjects:	Attention deficit hyperactivity disorder Dopamine Hyperactivity Neurodevelopmental disorders
Online Access:	Get full text
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Summary:	Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic paradoxical response to drugs affecting the dopaminergic system. However, the underlying pathophysiology of ADHD and how this relates to dopaminergic transmission remains to be fully understood. Sorcs2 mice uniquely recapitulate symptoms reminiscent of ADHD in humans. Here, we show that lack of SorCS2 in mice results in lower sucrose intake, indicating general reward deficits. Using in-vivo recordings, we further find that dopaminergic transmission in the ventral tegmental area (VTA) is shifted towards a more regular firing pattern with marked reductions in the relative occurrence of irregular firing in Sorcs2 mice. This was paralleled by abnormal acute behavioral responses to dopamine receptor agonists, suggesting fundamental differences in dopaminergic circuits and indicating a perturbation in the balance between the activities of the postsynaptic dopamine receptor DRD1 and the presynaptic inhibitory autoreceptor DRD2. Interestingly, the hyperactivity and drug response of Sorcs2 mice were markedly affected by novelty. Taken together, our findings show how loss of a candidate ADHD-risk gene has marked effects on dopaminergic circuit function and the behavioral response to the environment.
ISSN:	2158-3188 2158-3188