TAAR8 in the Brain: Implications for Dopaminergic Function, Neurogenesis, and Behavior

Abstract

Background/Objectives: G protein-coupled trace amine-associated receptors (TAARs) belong to a family of biogenic amine-sensing receptors. TAAR1 is the best-investigated receptor of this family, and TAAR1 agonists are already being tested in clinical studies for the treatment of schizophrenia, anxiety, and depression. Meanwhile, other TAARs (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9 in humans) are mostly known for their olfactory function, sensing innate odors. At the same time, there is growing evidence that these receptors may also be involved in brain function. TAAR8 is the least studied TAAR family member, and currently, there is no data on its function in the mammalian central nervous system. Methods: We generated triple knockout (tTAAR8-KO) mice lacking all murine Taar8 isoforms (Taar8a, Taar8b, and Taar8c) using CRISPR-Cas9 technology. In this study, we performed the first phenotyping of tTAAR8-KO mice for behavioral, electrophysiological, and neurochemical characteristics. Results: During the study, we found a number of alterations specific to tTAAR8-KO mice compared to controls. tTAAR8-KO mice demonstrated better short-term memory, more depressive-like behavior, and higher body temperature. Also, we observed changes in the dopaminergic system, brain electrophysiological activity, and adult neurogenic functions in mice lacking Taar8 isoforms. Conclusions: Based on the data obtained, it can be assumed that the physiological TAAR8 role is not limited only to the innate olfactory function, as previously proposed. TAAR8 could be involved in brain function, in particular in dopamine function regulation.

Keywords: TAAR; TAAR8; adult neurogenesis; depression; dopamine; short-term memory; trace amine; triple knockout.

Figure 1

Taar8a expression in the rat brain. RT-qPCR was performed on total RNA isolated from structures obtained from adult male rats (n = 4) using oligonucleotide primers for the Taar8a gene. Nucleotide sequencing confirmed the specificity of the PCR product. Data are presented as mean ± SEM. b.olf, olfactory bulb; PFC, prefrontal cortex; N.acc, nucleus accumbens; VTA, ventral tegmental area; hipp, hippocampus; s.nigra, substantia nigra; m.obl, medulla oblongata.

Figure 2

Behavioral profile of tTAAR8-KO mice. (A–D) Open field with novel object test: (A) total time and (B) number of interactions with two objects during the first day; (C) total time and (D) number of interactions with the novel object compared to the familiar one during the second day of the test. (E) Time spent in the novel arm compared to the familiar one in the T-maze test. * p < 0.05, ** p < 0.01, *** p < 0.001, Mann–Whitney test. (F) Stress-induced hyperthermia test. I—the first measurement; II—temperature measured 15 min after the first measurement; III—temperature measured 30 min after the first measurement. *** p < 0.001, 2-way ANOVA. (G,H) Forced swimming test: (G) latency of immobilization and (H) time of immobilization. *** p < 0.001, **** p < 0.0001, Mann–Whitney test. All results are shown as mean ± SEM.

Figure 3

Evaluation of the effectiveness of sensorimotor gating in tTAAR8-KO and control mice in the prepulse inhibition test. (A) Amplitude of startle reflex in response to pulse and paired (prepulse and subsequent pulse) stimuli; (B) value of prepulse inhibition. **** p < 0.0001, #### p < 0.0001, Mann–Whitney test. All results are shown as mean ± SEM.

Figure 4

Electrophysiological power spectra in the brain regions of tTAAR8-KO vs. control mice. (A) Power spectral density of the local field potential in the striatum (Str). (B) Power spectral density of the primary sensory cortex (S1) electrocorticogram. (C) Power spectral density of the primary motor cortex (M1) electrocorticogram. Blue and black lines—the power spectra of tTAAR8-KO and control mice, respectively; dotted lines—standard error of the mean (SEM). *** p < 0.001, **** p < 0.0001, two-way ANOVA with the Sidak post hoc test.

Figure 5

Alterations in DA metabolism in tTAAR8-KO mice. (A–C) Tissue level of DA, HVA, and HVA/DA rate in the frontal cortex of control and tTAAR8-KO mice. (D–F) Tissue level of DA, HVA, and HVA/DA rate in the striatum of control and tTAAR8-KO mice. DA—dopamine, HVA—homovanilinic acid. * p < 0.05; ** p < 0.01, Mann–Whitney test. All results are shown as mean ± SEM.

Figure 6

TH⁺ cell numbers in substantia nigra pars compacta (A) and ventral tegmental area (B) in tTAAR8-KO and control mice. TH—tyrosine hydroxylase, SNpc—substantia nigra pars compacta, VTA—ventral tegmental area. * p < 0.05, Mann–Whitney test. All results are shown as mean ± SEM.

Figure 7

DCX⁺ neuroblast-like cell density in the subventricular zone of the lateral ventricle (A) and in the subgranular zone of the dentate gyrus (B) in tTAAR8-KO and control mice. DCX—doublecortin; SVZ—subventricular zone; SGZ—subgranular zone. * p < 0.05, Mann–Whitney test. All results are shown as mean ± SEM.