A tardive dyskinesia drug target VMAT-2 participates in neuronal process elongation

Tardive dyskinesia involves involuntary movements of body parts and is often observed in individuals taking antipsychotics for extended periods. Initial treatment strategies include reducing medication dosage, switching medications, or using drugs to suppress symptoms. One of the therapeutic targets for tardive dyskinesia is vesicular monoamine transporter-2 (VMAT-2, also known as solute carrier family 18 member A2 [SLC18A2]), which functions as an energy-dependent transporter of monoamines. The therapeutic drugs are used during adulthood, when neurons are maturing. For the first time, we report that treatment with a chemical VMAT-2 inhibitor reduces neuronal process elongation, a phenomenon commonly observed during development. Treatment with the inhibitors reserpine or tetrabenazine decreased process elongation in primary cortical neurons, and similar results were obtained in N1E-115 neuronal model cells undergoing process elongation. Knockdown of VMAT-2 using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas13-fitted guide RNA also reduced process elongation. However, treatment with reserpine or tetrabenazine did not affect the morphology of mature processes. Notably, treatment with hesperetin, a citrus flavonoid with neuroprotective effects, was able to restore the reduced process elongation induced by these inhibitors or VMAT-2 knockdown. The underlying molecular mechanism appeared to involve neuronal differentiation-related Akt kinase signaling. These results suggest that VMAT-2, as a drug target for tardive dyskinesia, plays a key role in process elongation and that some inhibitory effects of VMAT-2-targeted drugs on its elongation may be mitigated by co-administering a neuroprotective molecule.