TAAR1 modulates cortical glutamate NMDA receptor function

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 PFCrelated 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.

Trace Amines and Their Receptors

“…As previously described, TAAR1 agonists can overcome both the hyperlocomotion and cognitive impairments induced by administration of NMDA receptor antagonists (Revel et al, 2011(Revel et al, , 2013. That TAAR1 can regulate glutamatergic transmission is further suggested by the significant alterations in glutamate transmission found in the prefrontal cortex of TAAR1-KO mice (Espinoza et al, 2015b), a location where TAAR1 mRNA is found in wild-type mice. Application of a patch-clamp electrophysiological approach to cortical slices revealed deficient glutamate NMDA receptor function in prefrontal cortex layer V pyramidal neurons of TAAR1-KO mice (Espinoza et al, 2015b).…”

“…That TAAR1 activation acutely regulates the glutamatergic system was supported by the observation that cultured cortical neurons treated with the TAAR1 agonist RO5166017 showed a modest increase in GluN1 expression and a significant increase in the phosphorylation of the Ser 896 residue (Espinoza et al, 2015b). Furthermore, TAAR1 expression was mapped to layer V cortical neurons in TAAR1-KO/dsRed knock-in rats, a recently developed transgenic rat model in which the fluorescent marker dsRed is expressed under the control of the TAAR1 promoter (Espinoza et al, 2015b). Since many cortical neurons in layer V project to the striatum, these data suggest that TAAR1 may modulate corticostriatal 594 glutamatergic transmission.…”

“…In contrast, the levels of GluN2A, the AMPA receptor subunit GluA1, and the phosphorylation status of postsynaptic density 95 (a postsynaptic protein critical to the proper organization and integrity of postsynaptic structures) were not altered in TAAR1-KO animals. That TAAR1 activation acutely regulates the glutamatergic system was supported by the observation that cultured cortical neurons treated with the TAAR1 agonist RO5166017 showed a modest increase in GluN1 expression and a significant increase in the phosphorylation of the Ser 896 residue (Espinoza et al, 2015b). Furthermore, TAAR1 expression was mapped to layer V cortical neurons in TAAR1-KO/dsRed knock-in rats, a recently developed transgenic rat model in which the fluorescent marker dsRed is expressed under the control of the TAAR1 promoter (Espinoza et al, 2015b).…”

“…That TAAR1 can regulate glutamatergic transmission is further suggested by the significant alterations in glutamate transmission found in the prefrontal cortex of TAAR1-KO mice (Espinoza et al, 2015b), a location where TAAR1 mRNA is found in wild-type mice. Application of a patch-clamp electrophysiological approach to cortical slices revealed deficient glutamate NMDA receptor function in prefrontal cortex layer V pyramidal neurons of TAAR1-KO mice (Espinoza et al, 2015b). This was associated with a decrease in the expression of the GluN1 and GluN2B subunits, as well as a decrease in the phosphorylation of the Ser 896 residue of GluN1.…”

In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1

“…Trace amine-associated receptor 1 (TAAR1) is a relatively recently discovered G protein-coupled receptor (Borowsky et al, 2001;Bunzow et al, 2001), which is expressed in monoaminergic brain regions and throughout the limbic system (Borowsky et al, 2001;Lindemann et al, 2008;Espinoza et al, 2015). TAAR1 is thought to play a role in regulating the limbic network, reward circuits, cognitive processes, and mood states and has been proposed as a pharmacological target for the treatment of mental disorders (Wolinsky et al, 2007;Lindemann et al, 2008;Miller, 2011;Revel et al, 2013) and psychostimulant dependence (Di Cara et al, 2011;Pei et al, 2014;Cotter et al, 2015;Jing and Li, 2015).…”