TAAR1 Modulates Cortical Glutamate NMDA Receptor Function.
Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, also play an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high-o5rder cognitive processes. TAAR1-selective ligands have shown potential antipsychotic, antidepressant, and pro-cognitive effects in experimental animal models; however, it remains unclear whether TAAR1 can affect PFC-related processes and functions. In this study, we document a distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that the development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions.
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Stefano
S
Espinoza
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Gabriele
G
Lignani
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
Lucia
L
Caffino
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Silvia
S
Maggi
1] Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy [2] Department of Pharmacology, St Petersburg State Medical University, Petersburg, Russia.
Ilya
I
Sukhanov
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Damiana
D
Leo
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Liudmila
L
Mus
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Marco
M
Emanuele
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Giuseppe
G
Ronzitti
Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Anja
A
Harmeier
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Lucian
L
Medrihan
1] Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy [2] Institute of Translational Biomedicine, Faculty of Biology, St Petersburg State University, St Petersburg, Russia.
Tatyana D
TD
Sotnikova
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Evelina
E
Chieregatti
Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Marius C
MC
Hoener
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Fabio
F
Benfenati
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Valter
V
Tucci
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
Fabio
F
Fumagalli
1] Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy [2] Institute of Translational Biomedicine, Faculty of Biology, St Petersburg State University, St Petersburg, Russia [3] Skolkovo Institute of Science and Technology (Skoltech) Skolkovo, Moscow region, Russia.
Raul R
RR
Gainetdinov
D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics*; D005260:Female; D007175:Impulsive Behavior / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010080:Oxazoles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism*; D012055:Reinforcement Schedule; D000095383:Trace Amine-Associated Receptors
D010080:Oxazoles; D010627:Phenethylamines; D043562:Receptors, G-Protein-Coupled; D017470:Receptors, Glutamate; D000095383:Trace Amine-Associated Receptors; C580579:4-(3,4-dichlorophenyl)-4,5-dihydrooxazol-2-ylamine; C583451:RO5166017