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.

Possible role of rare variants in Trace amine associated receptor 1 in schizophrenia

“…However, these agonists did not induce catalepsy or weight gain in various rodent and primate models (Revel et al, 2013b). In other studies on such knock-out mice, NMDA/AMPA ratio is altered as a result NMDA receptor dependent synaptic deficits; GluN1 and GluN2B subunits of NMDA receptors were also shown to be decreased along with behavioral abnormalities (Espinoza et al, 2015b). In yet another study a higher number of high affinity DRD2 receptors and higher expression of DRD2 in post-synaptic neurons and consequently activation of related G protein-independent pathway (AKT/GSK3) in the basal condition were reported (Espinoza et al, 2015a).…”

Trace amine-associated receptor 1 regulation of methamphetamine-induced neurotoxicity

“…The expression and phosphorylation of the GluN1 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptors, in both the striatum and the prefrontal cortex (PFC), is lower in Taar1 -KO mice compared to Taar1 -WT mice (Espinoza et al , 2015b;Sukhanov et al , 2016). However, when amphetamine is administered, striatal expression and phosphorylation of GluN1 are increased only in Taar1 -KO mice.…”

Neuroscience of Compulsive Eating Behavior

“…Similarly, in animal studies, the Sig 1 R, a receptor involved in alcohol and drug reinforcement (Sabino et al, 2009 , 2017 ), was upregulated in prefrontal cortical brain regions following limited access to a palatable diet, and peripheral administration of a Sig 1 R antagonist blocked binge and compulsive-like eating (Cottone et al, 2012 ). TAAR1, a receptor expressed in the striatum and prefrontal cortices is activated by trace amines and has been shown to modulate cortical glutamate and dopaminergic transmission (Leo et al, 2014 ; Espinoza et al, 2015 ). Protein expression of TAAR1 is decreased in the medial PFC of compulsive-like, binge-eating rats, and TAAR1 agonism injected into the infralimbic cortex blocked excessive intake of palatable food (Figure 2C ; Ferragud et al, 2017 ).…”