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.2015 Aug;40(9):2217-27.
doi: 10.1038/npp.2015.65. Epub 2015 Mar 9.

TAAR1 Modulates Cortical Glutamate NMDA Receptor Function

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TAAR1 Modulates Cortical Glutamate NMDA Receptor Function

Stefano Espinoza et al. Neuropsychopharmacology.2015 Aug.

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.

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Figures

Figure 1
Figure 1
Deletion of TAAR1 increases the amplitude and kinetics of evoked excitatory postsynaptic currents in layer V pyramidal neurons of the mouse frontal cortex. (a, right panel) The expression of the red fluorescent protein dsRed under the rat TAAR1 promoter in the layer V of PFC of transgenic TAAR1 KO dsRed rats. Representative images were taken using the overlay of the bright-field and dsRed channel from the layer V of PFC of transgenic TAAR1 KO dsRed rats (a, right panel, bottom) and WT rats (a, right panel, top). (a, left panel) Nissl-stained coronal section of mouse brain slice containing the medial prefrontal cortex (mPFC; box) in which patch clamp experiments were performed (a). Current-clamp protocol and representative traces of action potentials induced by the injection of 200 pA (b). Action potential frequencyvs injected current relationship (F/I curve) and resting membrane potential (c), maximal firing rate, mean firing frequency, current threshold, and input resistance (d) were measured in WT and TAAR1-KO mice. (e) Representative traces of evoked excitatory postsynaptic currents from layer V pyramidal neurons recorded upon stimulation of layer III neuron fibers in both WT and TAAR1-KO mice. (f) Amplitude, rise time, and decay time of evoked excitatory postsynaptic currents were altered in TAAR1-KO compared with WT neurons. Data represent means±SEM.N=8–12 cells per group andN=3–4 mice per group. *p<0.05; **p<0.01. Student’s unpaired two-tailedt-test.
Figure 2
Figure 2
TAAR1 regulates NMDA receptor number/efficiency in layer V mPFC neurons in mice. Representative traces of evoked AMPA (−70 mV) or NMDA (+60 mV) excitatory postsynaptic currents from layer V pyramidal neurons recorded upon stimulation of layer III fibers (a). The NMDA/AMPA ratio decreases in TAAR1-KO neurons with respect to WT neurons (b). Representative traces of miniature NMDA excitatory postsynaptic currents from both WT and TAAR1-KO layer V mPFC neurons (c). TAAR1-KO neurons show a decrease in NMDA miniature postsynaptic current amplitude and frequency (d and e). Data represent means±SEM.N=6–10 per groupN=3–4 mice per group. **p<0.01 Student’s unpaired two-tailedt-test.
Figure 3
Figure 3
NMDA receptor composition is altered in the prefrontal cortex of mice lacking TAAR1. Western blot densitometric analysis of the prefrontal cortex extracts from WT and TAAR1-KO mice. Synaptosomal fractions were separated from the whole lysate and then analyzed by gel electrophoresis. Antibodies against GluN1 (a), p-S896- GluN 1 (a), p-S897- GluN 1 (a), GluN 2B (b), p-S1303- GluN 2B (b), GluN 2A (b), GluA1 (c), p-S831-GluA1 (c), and PSD-95 (c) were used. Actin was used as the loading control for the densitometric analysis. Results were normalized to their respective WT controls. Data represent means±SEM.N=10–15 per group. *p<0.05; **p<0.01. Student’s unpaired two-tailedt-test.
Figure 4
Figure 4
TAAR1-KO mice display perseverative and impulsive behaviors in home cage. Graphical representation of the task. Fix-Interval (FI) task (a) presents two hoppers (right ‘R’ and left ‘L’) in which a light signal of two seconds (L=2) declares the start of the trial. The target time (T) is fixed to 10 s. The probability of trial to occur in ‘L’ location is 100% (P(L)=1). Peak-Interval (PI) task (b) introduces probe trials (Lp) that are randomly intermixed to normal trials with 20% of probability (p(Lp)=0.2) to occur (left panel). Example of normalized response curve during probe trials (right panel). The circadian profile of the nose-poke (NP) activity (c) exhibits significant genotype (two-way ANOVA: F(1,143)=13.71, ***p<0.001) difference during the dark phase (19–7 h). (c). Boxplots above the curves show no difference in the circadian periodicity for WT and TAAR1-KO mice (c). The circadian trend of the error rate (d) was significantly different within genotype and between light and dark phases (two-way ANOVA for WT: F(1,143)=40.67,p<0.001; for KO: F(1,143)=64.96,p<0.001), but not between genotypes (F(1,287)=0.47,p=0.49) as summarized in the histogram above the curve. Cumulative distribution function (CDF) of the error rate along the time (e). Significant difference of the total errors between genotypes during the first 3 h of the first dark phase (19–21),p=0.04. No difference between genotypes in the subsequent intervals (p⩾0.05). Analysis of the actual inter-trials (AITs) (f) revealed a difference between genotypes along 24 h (two-way ANOVA: F(1,287)=4.5,p=0.03) that was accentuated during the dark phase (F(1,143)=8.81,p=0.003). Bonferronipost hoc analysis does not reveal significant difference between each time point. Analysis of START (S1) and STOP (S2) responses (g). During the dark phase, the STOP times changed significantly across days (two-way ANOVA: F(4,56)=3.64,p=0.01). The genotype effect was also significant (F(1,59)=5.35,p=0.02). There was no difference in the START time. Normalized response rate during probe trials in the first and last days (h). Peak times were significantly different between genotypes (F(1,59)=4.19,p=0.04) and showed significant changes over time (F(4,56)=3.05,p=0.02) (i). The right NPs during the AITs, along the 24 h, revealed a difference between genotypes (F(1,96)=4.44,p=0.03) (j). All the data are shown as mean±SEM per group (N=6 per group for both WT and TAAR1-KO mice). *p<0.05; **p<0.005; ***p<0.001.
Figure 5
Figure 5
Systemic administration of selective TAAR1 agonists reduces impulsivity in a FI 30 s test in normal mice RO5166017 and RO5203648 decreased the number of correct premature responses in C57Bl/6J mice. ((a and c); F(3,28)=4.078p<0.05 and F(3,26)=8.029p<0.05, respectively).Post hoc analyses (Bonferroni’s test) revealed that this TAAR1 agonist effect was statistically significant at the dose of 1.0 mg/kg for RO5166017 and at the doses of 0.1 and 0.3 mg/kg for RO5203648. Activation of TAAR1 receptors did not affect significantly post-reinforcement pause (F(3,28)=1.967p=0.14; F(3,26)=2.506p=0.08, RO5166017 and RO5203648, respectively) (b and d). All the data are shown as mean±SEM.N=12 per group. RO5203648 at dose 0.3 mg/kg was able to reduce the number of correct premature responses in WT (p<0.05) but not in TAAR1-KO animals (e). Similarly, RO5203648 increased post-reinforcement pause in WT (p<0.01) but not in TAAR1-KO mice (f). All the data are shown as mean±SEM.N=10 (WT) and 8 (KO) per group. *p<0.05; **p<0.01. One-way ANOVA with Bonferronipost hoc test.
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