Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia

Area of Science:

• Neuroscience
• Molecular Psychiatry
• Computational Neuroscience

Background:

• Schizophrenia is associated with deficient gamma oscillations in the prefrontal cortex (PFC), potentially due to impaired inhibitory drive from parvalbumin-expressing interneurons (PVIs).
• RNA binding fox-1 homolog 1 (Rbfox1) regulates PVI inhibitory function, partly through its cytoplasmic isoform's control over vesicle associated membrane protein 1 (Vamp1) levels and subsequent GABA release probability.

Approach:

• Investigated the Rbfox1-Vamp1 pathway in PFC PVIs from schizophrenia patients and controls using multi-label in situ hybridization and immunohistochemistry.
• Quantified cytoplasmic Rbfox1 protein and Vamp1 mRNA levels in PVIs.
• Employed a computational network model to simulate the impact of altered GABA release probability on gamma oscillations.

Key Points:

• Significantly lower cytoplasmic Rbfox1 protein levels were found in PFC PVIs of individuals with schizophrenia.
• Vamp1 mRNA levels were also reduced in schizophrenia PVIs and correlated with lower Rbfox1 protein.
• Simulations demonstrated that reduced GABA release probability disrupts network synchrony, decreasing gamma power.

Conclusions:

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