TPH2 knockout impairs skilled motor performance and alters striatal dopamine metabolism in female rats

Tryptophan hydroxylase 2 knockout (TPH2-KO) rats lack serotonin (5-HT) specifically in the central nervous system (CNS). While previous research has focused on limbic system-related behaviors, the intrinsic effects of CNS 5-HT depletion on baseline motor control and their neurochemical basis remain incompletely understood. Here, we compared the sensorimotor performance of TPH2-KO and wild-type (WT) female rats using a battery of behavioral tests and assessed monoamine content in key CNS motor regions via HPLC.

TPH2-KO rats exhibited increased slips on the beam walking test and increased locomotor speed in kinematic analysis. Monoamine tissue content analysis of TPH2 knockout rats revealed a double dysregulation in both 5-HT and dopamine (DA) regulation in the CNS. DA levels were markedly reduced in the striatum and, even more severely, in the medulla oblongata, accompanied by elevated metabolite‑to‑DA ratios.

This dual monoamine disruption likely contributes to the observed alterations in locomotor speed and precision motor control, without evidence of gross motor coordination or balance deficits in the rotarod and horizontal ladder tests. Our findings reveal a novel motor phenotype in TPH2‑KO rats and demonstrate the power of the homozygous TPH2 knockout. This broadens the model not only for major depression research, but also highlights the potential relevance of TPH2‑KO rats for studying serotonin‑associated mechanisms of locomotor speed regulation and motor precision.

The research was supported by research resource center «Molecular and cell technologies» of St. Petersburg State University. Breeding and support of TPH2-KO and WT rats was performed by the Resource Center Vivarium of St.

Petersburg State University, St. This work was supported by the grant of the state program of the «Sirius» Federal Territory «Scientific and technological development of the «Sirius» Federal Territory» (Agreement No. 18–03 date 10 September 2024, raw kinematic data analysis) (to P.E.M.) and the project ID: 148723091 (to R.R.G.) of the St. These authors contributed equally to the study: Ilya Zhukov and Valentina Sviridova.

Institute of Translational Biomedicine, St. Petersburg State University, 199034, St. Petersburg, Russia Ilya Zhukov, Daria Shitc & Raul Gainetdinov Institute of Experimental Medicine, Acad.