Finding ways to reverse the genetic cause of bad stress responses in mice

Everyone occasionally faces stress, whether at school, at work, or during a global pandemic. However, some cannot cope with others like others. In a few cases, the cause is genetic. In humans, mutations in the OPHN1 gene cause a rare X-related disease that involves poor stress tolerance.

Professor Linda Van Aelst of the Cold Spring Harbor Laboratory (CSHL) seeks to understand the factors that cause certain individuals to respond poorly to stress. She and her lab studied the murine Ophn1 gene, analogous to the human gene, which plays a crucial role in the development of brain cell connections, memory and stress tolerance. When Ophn1 was removed in a particular part of the brain, mice expressed helpless behaviors similar to depression. Researchers have found three ways to reverse this effect.

To test for stress, the researchers placed the mice in a two-bedroom cage with a door in between. Conventional mice run away from the room giving them a slight shock to their legs. But animals missing Ophn1 sit helplessly in that room without trying to leave. Van Aelst wanted to understand why.

Her lab has developed a way to delete the Ophn1 gene in different regions of the brain. They found that removal of Ophn1 from the prelimbic region of the medial prefrontal cortex (mPFC), an area known to affect behavioral responses and sensations, induced a helpless phenotype. The team then discovered which brain circuit was disrupted by deleting Ophn1, creating excessive activity in a region of the brain and eventually a helpless phenotype.

Understanding the circuit

Pyramidal neurons are central to this brain circuit. If they shoot too much, the mouse becomes helpless.

The second cell, the interneuron, regulates the activity of the pyramidal neuron, taking care not to shoot too much.

These two cells reciprocate with each other, creating a loop.

Ophn1 controls a specific protein, RhoA kinase, within this feedback loop that helps regulate and balance activity.

Van Aelst found three agents that reversed the helpless phenotype. Fasudil, an inhibitor specific for RhoA kinase, mimicked the effect of missing Ophn1. The second drug suppresses the excess activity of pyramidal neurons. The third drug awakens interneurons to inhibit pyramidal neurons.

So, if you manage to restore proper activity in the medial prefrontal cortex, then you could save the phenotype. It was actually very exciting. It should be open to everyone. You never know. Everything is surprising. “

Linda Van Aelst, CSHL professor

Van Aelst hopes that understanding the complex feedback behind the stress reactions associated with Ophn1 will lead to better treatments for stress in humans.


Cold Spring Harbor Laboratory

Journal reference:

Wang, M., and others. (2021) Oligophrenin-1 moderates behavioral responses to stress by regulating the activity of interval parvalbumin in the medial prefrontal cortex. Neuron.