BACKGROUND: Psychiatric disorders and antipsychotics are associated with impaired neuroplasticity, while physical exercise has been reported to enhance neuroplasticity and improve cognitive and affective processes. Therefore, this study hypothesizes that voluntary exercise can enhance synaptic plasticity in juvenile rats disrupted by risperidone, a commonly prescribed antipsychotic for pediatric patients. METHODS: Thirty-two juvenile female rats were randomly assigned to Vehicle+Sedentary, Risperidone (0.9mg/kg
b.i.d)+Sedentary, Vehicle+Exercise (three hours daily access to running wheels), and Risperidone+Exercise groups for four week treatment. Brains were collected for further analysis. RESULTS: In the hippocampus, the mRNA expressions of Bdnf, Ntrk2, and Grin2b were increased by risperidone and exercise intervention. Exercise upregulated expression of Grin1 and Grin2a. Syn1 and Syp mRNA expression were enhanced by exercise in the risperidone-treated group. The expression of both Mfn1 and Drp1 mRNA were decreased by risperidone-only treatment. In the prefrontal cortex, Bdnf and Dlg4 expression was upregulated by exercise, while the Ntrk2 expression was reduced by risperidone and reversed by exercise. The Mfn1 mRNA expression was decreased by risperidone with or without voluntary exercise. The risperidone-decreased Ppargc1α gene expression was enhanced by exercise. CONCLUSION: Risperidone affects synaptic plasticity through a complex mechanism in female juvenile rats: enhancing certain key genes in the hippocampus while inhibiting genes essential for mitochondrial function. In line with our hypothesis, voluntary exercise promotes genes beneficial for synaptic plasticity and enhances specific genes reduced by risperidone, in female juvenile rats.