Nerve cell miswiring linked to depression

Mouse study identifies gene needed for proper assembly of serotonin circuitry

mouse brain

ALL TANGLED UP  In a healthy mouse (left), nerve cells (white) that release serotonin extend through the hippocampus. But when a specific gene is knocked out, those nerve cell wires clump together (right).

T. Maniatis/Columbia's Zuckerman Institute

Researchers have pinpointed a gene that keeps important brain cells in mice from crossing their wires, providing a possible link between brain wiring and mood disorders like depression.  

Without the gene, called Pcdhαc2, mice acted more depressed, researchers report April 28 in Science.

Nerve cells, or neurons, that produce the chemical messenger molecule serotonin extend long projections called axons to various parts of the brain. Serotonin released from the tips of the axons signal other neurons in these target areas to influence mood and other aspects of behavior. For efficient signaling, the axon tips must be properly spaced.

In the new work, scientists from New York City, St. Louis and China found that such spacing is disrupted in mice lacking the Pcdhαc2 gene. As a result, serotonin-signaling circuits are not properly assembled and the mice exhibited behaviors indicating depression.

Pcdhαc2 is found in a cluster of genes that contain the blueprints for proteins that protrude from the surface of cells. These proteins work like ID cards, says study coauthor Joseph Dougherty, a neurogeneticist at Washington University School of Medicine in St. Louis. As serotonin neuron axons branch out through the brain, they can recognize other axons carrying identical IDs and spread out to keep out of each other’s paths. This process, called tiling, evenly spaces the axons in their target areas within the brain.

But for mice in which the whole gene cluster was deleted, serotonin axons don’t keep their distance from each other. They trip each other up, which prevents the axons from fully extending through the brain and delivering the usual doses of serotonin, says Tom Maniatis, a study coauthor and molecular neuroscientist at Columbia University.

Uneven serotonin distribution affected the mice’s behavior. One test forced mice to swim for an extended period of time; mice with the cluster deleted were more likely to give up on swimming for survival. Other tests found no problem with the mutant mice’s muscles and movement, suggesting that mental state caused the surrendering behavior.

Maniatis and colleagues found that deleting one group of genes in the cluster didn’t cause the axon tangling, leaving two possible suspects. Of those two, only the protein coded by the Pcdhαc2 gene was found in the serotonin neurons.

The exact mechanism for how the protein keeps the axons in line still isn’t known, says Maniatis. But researchers think something within the protein repulses other proteins with the same ID card, keeping the axons far enough apart that they don’t tangle. 

What’s more clear, says Dougherty, is how disabling this gene can cause mice to behave in a way that is reminiscent of depression.

Sean Millard, a neuroscientist at the University of Queensland School of Biomedical Sciences in Australia, researches fly genes that influence neuron spacing. This genetic finding in mice is consistent with what’s been found in flies, Millard says. “It’s really nice to see that similar mechanisms are working in higher organisms.”

Further research would look at whether mutations of the same gene in humans could contribute to depression. The implications of neuron wiring in this study may also point researchers in a new direction for research into psychiatric disorders connected to serotonin. Many previous studies have focused on how serotonin is transmitted and synthesized, as well as the genes that control levels of the chemical. Instead, “maybe we should be looking at genes that regulate serotonin wiring,” Dougherty says.  

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