Homer prevents stress-induced cognitive deficits

Lack of membrane protein Homer-1 in the brain causes learning problems in mice

February 26, 2013

Before examinations and in other critical situations, we need to be particularly receptive and capable of learning. Acute exam stress and stage fright, however, cause learning blockades and reduced memory function. Scientists from the Max Planck Institute of Psychiatry in Munich have now discovered a mechanism responsible for these cognitive deficits functioning independently of stress hormones. In animal studies, the researchers have shown that social stress reduces the volume of Homer-1 in the hippocampus – a region of the brain playing a central role in learning. This specific protein deficiency leads to altered neuronal activity followed by deterioration in the animals’ learning performance. In the experiments, it was possible to prevent the cognitive deficit by administering additional volumes of the protein to the mice. This suggests that Homer-1 might become a key molecule for the development of drugs against stress-induced cognitive deficits.

The black mouse ("intruder") undergoes social stress while being heavily attacked by the home cage white mouse.

Klaus Wagner, scientist at the Max Planck Institute of Psychiatry, studied the learning behavior of mice that had been subjected to severe stress. He exposed the animals to social stress – a pressure also frequently experienced by humans today. For five minutes, a male mouse was placed in the cage of an aggressive member of the same species. The latter tried to banish the “intruder” by attacking it vehemently. Unlike in nature, the test mouse was unable to flee from the cage and thus under severe stress, as substantiated by measurements of the stress hormones in its blood.

Following a period of eight hours during which the animal had the opportunity to recover in its own cage, its behavior was examined. While the mouse’s motivation, activity and sensory functions were not impaired, it displayed clear deficits in its learning behavior. A single five-minute situation of social stress had been enough to impair the animal’s learning performance hours later.

The researchers at the Max Planck Institute then tried to identify the mechanisms responsible for these cognitive deficits. They identified the protein Homer-1, the concentration of which specifically declines in the hippocampus after exposure to stress. Interestingly, the isolated increase in stress hormone levels without an actually experienced stress situation neither induces a learning deficit nor a decline in Homer-1 protein levels. Thereby, the scientists show that experienced stress activates additional – stress hormone independent – regulatory systems to affect learning and memory. In detail, Homer-1 modulates the communication of neuronal synapses through its interaction with the neurotransmitter glutamate and its receptor. Whenever the concentration of Homer-1 in the hippocampus decreases after exposure to stress, the natural receptor activity is severely disrupted and learning capacity declines. By increasing the Homer-1 concentration again, the researchers were able to prevent this effect.

Mathias Schmidt, Research Group Leader at the Max Planck Institute of Psychiatry, interprets the results as follows: “In our study, we demonstrated the regulation of glutamate-mediated communication in the hippocampus largely unaffected by stress hormones which directly controls learning behavior. The molecule Homer-1 assumes a key role in this process and will hopefully provide new possibilities for targeted pharmaceutical intervention to avoid cognitive deficits.”

BM/HR

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