Surrogate GPR139 Agonists Reverse Short‐Term Startle Habituation Impairment in Larval Zebrafish

GPR139, an orphan G-protein coupled receptor predominantly expressed in the habenula, has recently been implicated in understanding neurobehavior and neuropsychiatric disorders. Surrogate agonists for human GPR139 have shown the potential to alleviate cognitive impairment associated with schizophrenia in rodent models and human clinical trials. Yet, the effect of GPR139 agonists on the neurophysiological properties of the habenula remains elusive. We examined the effect of GPR139 agonists (JNJ-63533054 and TAK-041) on short-term startle habituation of 6-day post-fertilization (dpf) larval zebrafish (Danio rerio) in an automated solenoid setup and on reversing the pharmacologically impaired startle habituation. GPR139 agonists enhanced startle habituation at the lowest tested concentrations, whereas moderate and highest concentrations delayed startle habituation. Furthermore, GPR139 agonists reversed the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801-induced startle habituation impairment. Using exponential decay curve fit analysis, we found that the lowest concentration of GPR139 agonists performed better than moderate and highest concentrations in reversing the MK-801-induced impairment of startle habituation. Using in vivo GCaMP calcium imaging and phosphorylated extracellular-signal-regulated kinase (pERK) as a proxy for neural activity, we found that GPR139 agonists exerted effects on the habenula activities at the habituated state but not during the spontaneous state (without startle habituation paradigm), suggesting the GPR139 agonists-evoked neural activation in the habenula is sensory stimuli-dependent. Moreover, both GPR139 agonists differently reduced MK-801-induced hyperexcitability of the habenula at both spontaneous and habituated states. Taken together, we showed that GPR139 agonists reverse startle habituation impairment caused by MK-801 via the normalization of hyperexcitability of zebrafish habenula.