Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Antipsychotic drugs show rapid initial effects but delayed full efficacy, suggesting underlying neuronal changes.
• Dopamine receptor type 2 (D₂R) antagonism is a key mechanism for antipsychotic action.

Purpose of the Study:

• To investigate the rapid molecular and cellular mechanisms underlying antipsychotic drug action.
• To elucidate the role of the Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway in mediating antipsychotic effects.

Main Methods:

• Primary striatal neurons and cultured cortical neurons were treated with haloperidol.
• Activation of the Akt/mTORC1 pathway was assessed by measuring protein phosphorylation (S6, 4E-BP).
• Proteomic mass spectrometry was used to analyze changes in protein synthesis.
• Neuronal morphology was quantified, and the effects of mTORC1 inhibition were evaluated.

Main Results:

• Haloperidol stimulated Akt and activated the mTORC1 pathway, increasing protein synthesis in D₂R-positive neurons.
• Acute haloperidol exposure led to increased abundance of cytoskeletal and translation machinery proteins.
• These proteomic changes correlated with enhanced neuronal morphological complexity, dependent on mTORC1.
• In vivo studies showed rapid morphological changes and increased cytoskeletal proteins in mouse cortical neurons.

Conclusions:

• Antipsychotic-induced activation of the mTORC1-dependent translation pathway rapidly enhances neuronal complexity.
• This mechanism provides insight into both the acute and long-lasting effects of antipsychotic medications.
• Targeting the mTORC1 pathway may offer novel therapeutic strategies for psychiatric disorders.