Altered learning, memory, and social behavior in type 1 taste receptor subunit 3 knock-out mice are associated with neuronal dysfunction.. Mus musculus

The type 1 taste receptor member 3 (T1R3) is a G protein-coupled receptor involved in sweet-taste perception. Besides the tongue, the T1R3 receptor is highly expressed in brain areas implicated in cognition, including the hippocampus and cortex. As cognitive decline is often preceded by significant metabolic or endocrinological dysfunctions regulated by the sweet-taste perception system, we hypothesized that a disruption of the sweet-taste perception in the brain could have a key role in the development of cognitive dysfunction. To assess the importance of the sweet-taste receptors in the brain, we conducted transcriptomic and proteomic analyses of cortical and hippocampal tissues isolated from T1R3 knock-out (T1R3KO) mice. The effect of an impaired sweet-taste perception system on cognition functions were examined by analyzing synaptic integrity and performing animal behavior on T1R3KO mice. Although T1R3KO mice did not present a metabolically disrupted phenotype, bioinformatic interpretation of the high-dimensionality data indicated a strong neurodegenerative signature associated with significant alterations in pathways involved in neuritogenesis, dendritic growth, and synaptogenesis. Furthermore, a significantly reduced dendritic spine density was observed in T1R3KO mice together with alterations in learning and memory functions as well as sociability deficits. Taken together our data suggest that the sweet-taste receptor system plays an important neurotrophic role in the extralingual central nervous tissue that underpins synaptic function, memory acquisition, and social behavior. Overall design: All animal procedures were approved by the Animal Care and Use Committee (ACUC) of the National Institute on Aging (NIA). T1R3 knockout mice (T1R3KO) were kindly provided by Dr. Charles Zuker (Columbia University) and were cross bred with wild type (WT) C57BL/6J mice (Jackson Laboratory) for at least 4 generations. All animals were kept in a 12 h light/dark cycle and received food (standard Harlan-Teklad chow: LM-485) and water ad libitum. A total of 10 to 20 mice (4-5 months of age) in each group were employed for behavioral, histological and protein expression analyses. 4-5month old animals were used in the experiments and euthanized right after the experiments. For post mortem tissue extraction, animals were humanely euthanized with isoflurane: specific organs/tissues were then carefully dissected, snap-frozen and stored at -80˚ C until further analysis RNA was isolated from cortical, hypothalamic, and hippocampal brain tissues from wildtype and T1R3 knockout (T1R3KO) C57BL/6J mice and used for transcriptomic analyses (N=3/group, 18 animals total).