Mitochondrial dysfunction linked to cortical under-connectivity, cognitive impairment

Under-connectivity, or too few connections in the brain, could be the underlying cause of brain disorders like autism and schizophrenia, according to a new study by researchers at the George Washington University Institute for Neuroscience in Washington, D.C. and published in the journal Neuron.

Working in models of DiGeorge/22q11 Deletion Syndrome, a common disorder with the highest known genetic association with diseases like schizophrenia and autism, the researchers defined the disruptions of cell and molecular functions that lead to altered development of nerve cells and their connections in the cerebral cortex. They associated these changes with behavioral deficits linked to neurodevelopmental disorders.

Using a mouse model, the research team first sought to confirm that under-connectivity, not over-connectivity, underlies behavioral deficits. They found that the integrity and efficiency of synapses in the cortex were diminished. The researchers looked at the cells making the connections. They found the cells were unhealthy due to dysfunctional mitochondria, long known to be the powerhouse of the cell.

The research team then tested the theory that mitochondria in these cells might be dysfunctional due to increased reactive oxygen species, oxygen molecules that roam freely through cells and cause extensive damage.

Finally, the team used antioxidant therapy to neutralize these dangerous oxygen "free radicals" to help restore mitochondrial function. This therapy not only fixed connectivity but fixed the behavioral deficits that happened as a result.

The team then looked at the 28 genes on chromosome 22 for which one of two copies is lost in individuals with DiGeorge/22q11 Deletion Syndrome. They focused on six of these 28 genes associated with mitochondria. They identified the Txrnd2 gene, which encodes an enzyme that neutralizes reactive oxygen in mitochondria, as a critical player in the growth and connectivity of the cortical cells that are under-connected.

The study provides the first evidence showing that individual nerve cells fail to make the right number of connections. The reason for this deficit is limited growth of key nerve cells in the cerebral cortex during early development, due to both genetics and mitochondrial dysfunction, researchers said.

This work confirms a well-known clinical hypothesis that under-connectivity is the basis of disorders like autism and schizophrenia, and offers safe, effective therapy that corrects both the pathology and behavioral impairment in a valid animal model of any neurodevelopment disorder.