Molecular mechanisms: Deletion moves inhibitory neurons

Loss of one copy of 22q11.2 — a chromosomal region linked to schizophrenia and autism — shifts the location of neurons that inhibit brain signals, according to a study published 6 November in Proceedings of the National Academy of Sciences¹.

The deletion also results in abnormally low levels of CXCR4, a protein involved in neuronal development and migration through the brain.

Postmortem brains from people with a deletion in 22q11.2 have misplaced neurons in the cerebral cortex, a brain region needed for most higher-order functions². They also have deficits in inhibitory neurons that release the chemical messenger gamma-aminobutyric acid (GABA). Several studies have linked defects in GABA and inhibitory neurons to autism.

In the new study, researchers looked at fluorescently labeled neurons in mice lacking one copy of the 22q11.2 region. These mice harbor parvalbumin neurons, one type of inhibitory neuron, in superficial brain regions, compared with deeper regions in controls.

These neurons also move differently than in controls and take an altered route through the developing brains of mutant mice, the study found.

The mutant mice also have 35 percent less CXCR4 than controls do. CXCR4 guides inhibitory neurons to their proper locations during development. Mice lacking one copy of this gene in parvalbumin neurons show the same abnormal neuron placement. Combining both mutations worsens the effect.

This suggests that the 22q11.2 deletion affects the brain partly through CXCR4, making it a candidate risk gene for schizophrenia and autism, the researchers say. 

References:

1:Meechan D.W. et al. Proc. Natl. Acad. Sci. USA 109, 18601-18606 (2012) PubMed

2:Kiehl T.R. et al. Cereb. Cortex 19, 153-164 (2009) PubMed