Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia

Area of Science:

• Neuroscience
• Molecular Biology
• Psychiatry

Background:

• Deficient gamma oscillations in the prefrontal cortex (PFC) are observed in schizophrenia, linked to impaired inhibitory drive from parvalbumin-expressing interneurons (PVIs).
• RNA binding fox-1 homolog 1 (Rbfox1) regulates PVI inhibitory drive, with its cytoplasmic isoform affecting target mRNA stability, including vesicle associated membrane protein 1 (Vamp1).
• Vamp1 mediates GABA release probability from PVIs, and Rbfox1 loss reduces Vamp1, impairing cortical inhibition.

Purpose of the Study:

• To investigate alterations in the Rbfox1-Vamp1 pathway within PVIs in the PFC of individuals with schizophrenia.
• To determine the functional impact of these alterations on gamma oscillations using computational modeling.

Main Methods:

• Multi-label in situ hybridization and immunohistochemistry were used on PFC tissue from 20 matched pairs of schizophrenia and comparison subjects.
• Cytoplasmic Rbfox1 protein and Vamp1 mRNA levels were quantified in PVIs.
• A computational network model simulated the effect of reduced GABA release probability on gamma power.

Main Results:

• Significantly lower cytoplasmic Rbfox1 protein levels were found in PVIs from individuals with schizophrenia.
• Vamp1 mRNA levels were also significantly lower in schizophrenia PVIs and correlated with Rbfox1 protein levels.
• Computational simulations demonstrated that reduced GABA release probability decreases gamma power by disrupting network synchrony.

Conclusions:

• The Rbfox1-Vamp1 pathway in PVIs is impaired in schizophrenia.
• This impairment likely contributes to the deficient PFC gamma oscillations observed in the illness.
• Findings highlight a novel molecular mechanism underlying cognitive deficits in schizophrenia.