The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar...

Area of Science:

• Neuroscience
• Psychiatry
• Genetics

Background:

• Schizophrenia (SZ) and bipolar disorder (BP) are highly heritable psychiatric disorders with shared genetic risks and clinical symptoms.
• Understanding the common neurobiological pathways linking these shared risks to clinical manifestations is crucial.

Purpose of the Study:

• To identify a common neurobiological mediator connecting polygenic risks to shared behavioral changes in SZ and BP.
• To investigate the role of the miR-124-3p-AMPAR pathway in mediating these shared aspects.

Main Methods:

• Examined miR-124-3p levels in neuronal cells and postmortem prefrontal cortex from SZ and BP patients.
• Developed a mouse model with upregulated miR-124-3p in the medial prefrontal cortex.
• Assessed changes in AMPA receptors (AMPARs) and excitatory synaptic transmission in the mouse model.

Main Results:

• miR-124-3p was upregulated in both SZ and BP patient samples and associated with shared polygenic risks.
• Upregulation of miR-124-3p in mice increased GRIA2-lacking calcium-permeable AMPARs.
• This led to altered AMPAR-mediated excitatory synaptic transmission and shared behavioral deficits.

Conclusions:

• The miR-124-3p-AMPAR pathway is a key common neurobiological mediator in SZ and BP.
• This pathway translates shared polygenic risks into common behavioral alterations observed in these psychotic disorders.