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

Area of Science:

• Neuroscience
• Pharmacology
• Behavioral Science

Background:

• GPR139, an orphan G-protein coupled receptor, is primarily found in the habenula and is linked to neurobehavior and neuropsychiatric disorders.
• GPR139 agonists have shown promise in preclinical and clinical studies for cognitive deficits in schizophrenia.
• The precise neurophysiological impact of GPR139 agonists on the habenula remains largely unexplored.

Purpose of the Study:

• To investigate the effects of GPR139 agonists (JNJ-63533054 and TAK-041) on startle habituation in larval zebrafish.
• To determine if GPR139 agonists can reverse N-methyl-d-aspartate (NMDA) receptor antagonist-induced impairments in startle habituation.
• To explore the influence of GPR139 agonists on habenula neural activity and its relationship with sensory stimuli.

Main Methods:

• Larval zebrafish (Danio rerio) were used to assess short-term startle habituation in an automated solenoid setup.
• The effects of GPR139 agonists and the NMDA antagonist MK-801 on habituation were evaluated.
• In vivo GCaMP calcium imaging and pERK staining were employed to measure neural activity in the habenula.

Main Results:

• Low concentrations of GPR139 agonists enhanced startle habituation, while higher concentrations impaired it.
• GPR139 agonists effectively reversed MK-801-induced deficits in startle habituation, with lower doses showing superior efficacy.
• GPR139 agonists modulated habenula activity in a sensory-dependent manner and reduced MK-801-induced hyperexcitability.

Conclusions:

• GPR139 agonists can reverse MK-801-induced startle habituation impairment in zebrafish larvae.
• The mechanism involves the normalization of habenula hyperexcitability.
• These findings highlight the potential of GPR139 modulation for treating conditions involving cognitive impairment and habenula dysfunction.