TAAR1 Modulates Cortical Glutamate NMDA Receptor Function

Stefano Espinoza, Gabriele Lignani, Lucia Caffino, Silvia Maggi, Ilya Sukhanov, Damiana Leo, Liudmila Mus, Marco Emanuele, Giuseppe Ronzitti, Anja Harmeier, Lucian Medrihan, Tatyana D. Sotnikova, Evelina Chieregatti, Marius C. Hoener, Fabio Benfenati, Valter Tucci, Fabio Fumagalli, Raul R. Gainetdinov

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

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.

Lingua originaleInglese
pagine (da-a)2217-2227
Numero di pagine11
RivistaNeuropsychopharmacology
Volume40
Numero di pubblicazione9
DOI
Stato di pubblicazionePubblicato - 16 ago 2015
Pubblicato esternamente

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