Dopamine transporter silencing in the rat

• Verfasst von: Reinwald, Jonathan Rochus [VerfasserIn]
• Verfasst von: Gass, Natalia [VerfasserIn]
• Verfasst von: Mallien, Anne S. [VerfasserIn]
• Verfasst von: Sartorius, Alexander [VerfasserIn]
• Verfasst von: Becker, Robert [VerfasserIn]
• Verfasst von: Sack, Markus [VerfasserIn]
• Verfasst von: Falfán‐Melgoza, Claudia [VerfasserIn]
• Verfasst von: Clemm von Hohenberg, Christian [VerfasserIn]
• Verfasst von: Leo, Damiana [VerfasserIn]
• Verfasst von: Pfeiffer, Natascha [VerfasserIn]
• Verfasst von: Middelman, Anthonieke [VerfasserIn]
• Verfasst von: Meyer-Lindenberg, Andreas [VerfasserIn]
• Verfasst von: Homberg, Judith R. [VerfasserIn]
• Verfasst von: Weber-Fahr, Wolfgang [VerfasserIn]
• Verfasst von: Gass, Peter [VerfasserIn]
• Titel: Dopamine transporter silencing in the rat
• Titelzusatz: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits
• Verf.angabe: Jonathan R. Reinwald, Natalia Gass, Anne S. Mallien, Alexander Sartorius, Robert Becker, Markus Sack, Claudia Falfan-Melgoza, Christian Clemm von Hohenberg, Damiana Leo, Natascha Pfeiffer, Anthonieke Middelman, Andreas Meyer-Lindenberg, Judith R. Homberg, Wolfgang Weber-Fahr and Peter Gass
• E-Jahr: 2022
• Jahr: 4 March 2022
• Umfang: 11 S.
• Fussnoten: Gesehen am 25.03.2024
• Titel Quelle: Enthalten in: Molecular psychiatry
• Ort Quelle: [London] : Springer Nature, 1997
• Jahr Quelle: 2022
• Band/Heft Quelle: 27(2022), 4, Seite 2329-2339
• ISSN Quelle: 1476-5578
• DOI: doi:10.1038/s41380-022-01471-4
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: ADHD
• Sach-SW: Bipolar disorder
• Sach-SW: Genetics
• Sach-SW: Neuroscience
• Sach-SW: Schizophrenia
• K10plus-PPN: 188421584X

Abstract

Silencing of dopamine transporter (DAT), a main controlling factor of dopaminergic signaling, results in biochemical and behavioral features characteristic for neuropsychiatric diseases with presumed hyperdopaminergia including schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and obsessive-compulsive disorder (OCD). Investigation of DAT silencing thus provides a transdiagnostic approach towards a systems-level understanding of common underlying pathways. Using a high-field multimodal imaging approach and a highly sensitive cryogenic coil, we integrated structural, functional and metabolic investigations in tandem with behavioral assessments on a newly developed preclinical rat model, comparing DAT homozygous knockout (DAT-KO, N = 14), heterozygous knockout (N = 8) and wild-type male rats (N = 14). We identified spatially distributed structural and functional brain alterations encompassing motor, limbic and associative loops that demonstrated strong behavioral relevance and were highly consistent across imaging modalities. DAT-KO rats manifested pronounced volume loss in the dorsal striatum, negatively correlating with cerebellar volume increase. These alterations were associated with hyperlocomotion, repetitive behavior and loss of efficient functional small-world organization. Further, prefrontal and midbrain regions manifested opposite changes in functional connectivity and local network topology. These prefrontal disturbances were corroborated by elevated myo-inositol levels and increased volume. To conclude, our imaging genetics approach provides multimodal evidence for prefrontal-midbrain decoupling and striato-cerebellar neuroplastic compensation as two key features of constitutive DAT blockade, proposing them as transdiagnostic mechanisms of hyperdopaminergia. Thus, our study connects developmental DAT blockade to systems-level brain changes, underlying impaired action inhibition control and resulting in motor hyperactivity and compulsive-like features relevant for ADHD, schizophrenia and OCD.