Objective: Rhes is a small GTP-binding protein highly enriched in the striatum, developmentally regulated by thyroid hormone, and by dopamine (DA) innervation in adult rat brain. Within the striatum, Rhes mRNA is localized in DA D1 and D2 receptors-bearing medium-sized projection neurons, as well as in large aspiny cholinergic interneurons, where it modulates DA-dependent transmission and signaling. Interestingly, recent findings showed that Rhes binds and activates mTORC1, a key modulator of several biological processes, including L-DOPA-induced dyskinesia.

Background: This study was aimed to evaluate the effect of Rhes deletion on the number of midbrain dopamine neurons, as well as nigrostriatal-sensitive motor behavior during aging in Rhes mutant mice.

Methods: Motor performance and coordination were evaluated using the beam-walking test. Three separate groups of Rhes^-/- and Rhes^+/+ (control) mice of 3, 6 and 12 months old were tested. Time to traverse the beam, number of steps and errors per step were recorded for each animal. Immunohistochemistry and stereological analysis of tyrosine hydroxylase (TH)-positive neurons in SNc were performed in 6 and 12-month-old Rhes^+/+ and Rhes^-/- mice.

Results: A significant decrease of total number and density of TH-positive neurons was found in 6 and 12 months old Rhes^-/- mice as compared with control Rhes^+/+ mice of the same age. Three, 6 and 12 months old Rhes-/- mice made significant higher number of steps to traverse the beam compared to Rhes^+/+ mice. Six and 12 months old Rhes^-/- mice spent significant longer time to traverse the beam compared to Rhes^+/+ mice. Moreover, 12 months old Rhes^-/- mice made significantly more errors per step in traversing the beam compared to Rhes^+/+ mice. Results showed that the motor performance and coordination of Rhes^-/- mice is worsen as compared with control mice and it is exacerbated with age.

Conclusions: Overall, these data demonstrated that lack of the Rhes gene in mutant mice results in subtle TH-positive neuron reduction, accompanied by deficits in nigrostriatal-dependent motor behavior.

At the XVI Meeting of Italian Society for Neuroscience – October 8-11, 2015 – Cagliari, Italy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-small-gtp-binding-protein-rhes-influences-midbrain-dopaminergic-neurons-behavioral-and-biochemical-studies/