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Breakthrough Magazine

Molecular memory

We often associate faulty memory with dementia or Alzheimer's — the elderly person who can't remember names or information. But when the brain's molecular process for encoding memory isn't working properly, the task of developing acceptable social behavior can be short circuited, as well, particularly for those with an autism spectrum disorder, schizophrenia or bipolar disorder.

We often associate faulty memory with dementia or Alzheimer’s — the elderly person who can’t remember names or information.

But when the brain’s molecular process for encoding memory isn’t working properly, the task of developing acceptable social behavior can be short circuited, as well, particularly for those with an autism spectrum disorder, schizophrenia or bipolar disorder.

“Most of what we think of as ‘socially acceptable behavior’ is not an innate ability,” says Michy Kelly, an assistant professor in the School of Medicine’s Department of Pharmacology, Physiology and Neuroscience. “It’s all learned. So if something breaks down in your ability to form memories of your social experiences, there’s no feedback loop that helps you learn what is and is not socially acceptable. You don’t remember that people don’t like it when you get too close or talk too loudly in their face, so you keep on doing it.”

Kelly’s research focuses on neural proteins that affect social behavior and a specific memory process called episodic memory that takes place in the hippocampus. Her lab group has been funded by the National Institutes of Health, the Brain and Behavior Research Foundation and the PhRMA Foundation.

“I’ve mostly been driven by fundamental questions of how the brain functions and what fails in neuropsychiatric dysfunction,” says Kelly, who began her career working in pharmaceutical research at Wyeth and Pfizer. “I’m interested in the molecular mechanisms that control memory and social behavior and how those mechanisms break down in disease states.”

Memory is created by changing how easily neurons communicate with each other across a specific circuit. For a memory to last minutes to hours, the brain only has to modify proteins that already exist within synapses, the connection points between nerve cells. However, for a memory to last hours to a lifetime, a signal has to make it all the way to the nerve cell’s nucleus to trigger the production of new molecules that are then sent all the way back to the synapses to “glue in” the memory.

With so many molecular mechanisms involved, it’s easy to understand why our long-term memory is so vulnerable to disease. The circuit that encodes memories for social experiences involves the hippocampus, a horse-shoe shaped area of the brain where many types of memory are processed.

“Think of a child on the autism spectrum. They seem unable to appreciate what is and is not socially-acceptable behavior. We believe this may be due, in part, to faulty memory encoding, which leaves him/her unable to form memories involving social cues,” Kelly says. “And it becomes a vicious cycle. We tend to ostracize those who don’t act normally, so they have even less opportunity to learn appropriate behavior. And social isolation starts to break down the molecular mechanisms in the brain even further.”

It turns out that the human brain doesn’t care if a person is actually isolated from human contact or if the person simply feels isolated — the biomarkers can look the same, Kelly says. Her lab has found enzymes in the hippocampus that could present promising targets for drug therapy to normalize episodic memory function and its corresponding role in learned social behavior.

“Our research shows that the enzyme PDE11A4 is required for rodents to form memories for social experiences. Not only does PDE11A4 modulate social behaviors, but social isolation seems to break down PDE11A4,” she says. “We have also shown that PDE11A4 controls how well rodents respond to lithium, a classic mood stabilizer used to treat patients with bipolar disorder.

“We have great hope that our findings will lead to new treatments for patients with schizophrenia, bipolar disorder or an autism spectrum disorder. PDE11A4 is only expressed in the hippocampus, mostly in the ventral/anterior portion, so we like it as a drug target. The restricted nature of PDE11A4 expression gives us hope that a PDE11A4 drug could provide symptom relief in the hippocampus without causing unwanted side effects elsewhere in the brain or body.”

“We hope what we’re learning will have relevance to autism, schizophrenia as well as memory and learning deficiencies,” Kelly says. “The whole reason I got inspired to pursue this line of research is the concept of the brain encoding memory. That’s a fascinating thing in itself.”

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