TY - JOUR

T1 - TAAR1 Modulates Cortical Glutamate NMDA Receptor Function

AU - Espinoza, Stefano

AU - Lignani, Gabriele

AU - Caffino, Lucia

AU - Maggi, Silvia

AU - Sukhanov, Ilya

AU - Leo, Damiana

AU - Mus, Liudmila

AU - Emanuele, Marco

AU - Ronzitti, Giuseppe

AU - Harmeier, Anja

AU - Medrihan, Lucian

AU - Sotnikova, Tatyana D.

AU - Chieregatti, Evelina

AU - Hoener, Marius C.

AU - Benfenati, Fabio

AU - Tucci, Valter

AU - Fumagalli, Fabio

AU - Gainetdinov, Raul R.

N1 - Publisher Copyright: © 2015 American College of Neuropsychopharmacology. All rights reserved.

PY - 2015/8/16

Y1 - 2015/8/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84937161968&partnerID=8YFLogxK

U2 - 10.1038/npp.2015.65

DO - 10.1038/npp.2015.65

M3 - Article

C2 - 25749299

AN - SCOPUS:84937161968

VL - 40

SP - 2217

EP - 2227

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 9

ER -