Researchers develop mouse with ‘off switch’ in serotonin-producing brain cells

August 1, 2011

Scientists at the National Institutes of Health (NIH) have developed a strain of mice with a built-in off switch that can selectively shut down the animals’ serotonin-producing cells, which make up a brain network controlling breathing, temperature regulation, and mood.

The researchers developed mice with a unique receptor on the surface of their serotonin-producing neurons.  Typically, cells communicate via chemicals that bind to receptors on their surfaces, with the molecules binding to their receptors.

The researchers added this special receptor to the mice’s serotonin-producing neurons using a genetic manipulation technique called intersectional genetics. They manipulated the animals’ genetic material so that it manufactured an additional receptor on the surface of its neurons: the animals’ serotonin-producing cells began to make a receptor not found in nature.  Rather than binding to a naturally occurring brain chemical, the receptor bound to a chemical compound manufactured in a laboratory, clozapine-N-oxide (CNO).

When CNO bound with the receptor, it deactivated only the serotonin cells, effectively switching off all communications in the serotonin network. CNO did not affect any other cells in the mouse brains or bodies.

The researchers found that when normal mice were exposed to carbon dioxide, they almost immediately began to breathe faster and more deeply. In contrast, mice with the receptor to CNO had a smaller response to carbon dioxide after their serotonin-producing neurons were switched off, and did not increase their breathing as much.  The mice with the receptor to CNO also could not regulate their body temperature as well as the normal mice, the researchers said.

The finding provides support for previous studies by NIH grantees implicating abnormalities in serotonin metabolism in the brainstem as playing a role in sudden infant death syndrome (SIDS), where infants are both unable to respond to breathing challenges and unable to regulate their body temperature, the researchers said.

Ref.: R. S. Ray et al., Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition, Science, 2011; 333 (6042): 637 [DOI: 10.1126/science.1205295]