Lombroso Lab: Learning, memory and the neuro-frontier

On Sunday, Yale’s Anlyan Center Auditorium played host to the National Association for Research in Schizophrenia and Depression annual symposium on current research as part of its Healthy Minds Across America initiative. The News caught up with one of the researchers, Paul Lombroso, director of the Yale molecular neurobiology laboratory — called the Lombroso Lab — to talk about his presentation at the symposium, his ongoing work and his plans for the future.

Q: What is the main research focus at the Lombroso lab?

A: Learning and memory — how we normally learn and how, unfortunately, sometimes we don’t learn. We study Fragile X syndrome [a mental retardation], Alzheimer’s and schizophrenia.

Q: Why those three?

A: Our laboratory has discovered that a particular protein called STEP removes glutamate receptors from synaptic membrane. These receptors are critical for learning to take place. When we turn a short-term memory into a long-term memory, the process we call consolidation, stimulation of glutamate receptors are required. These receptors are tightly regulated — for example, they are moved to the active sites, called synapses, in order to function, and can also be removed from these sites of active neurotransmission. This is termed “trafficking” and has been an area of active study in many laboratories around the world. As one can imagine, the removal of these critical receptors puts the break on any new learning.

Q: And so what happens to the neurobiology of someone suffering from one of those three diseases?

A: In Fragile X, the STEP protein is inappropriately expressed, meaning too much of it gets translated. Excessive levels of STEP lead to the removal of these glutamate receptors. In Alzheimer’s disease, STEP once again is activated, and again leads to the inappropriate removal of glutamate receptors. In both cases, this causes a disruption to synaptic connection and is thought to lead to the destruction that occurs in cognitive function.

Q: And what work has the Lombroso lab done regarding this?

A: Lombroso lab has recently discovered that STEP is activated in several disorders, mainly Fragile X syndrome. Advances in the disorders have been made over the last few years, but I’ve been here for 20 years. [We] discovered STEP, discovered whole families of proteins, began to identify substrates they act on — our most recent discovery is that STEP acts on glutamate, and [this information] led to looking at disorders.

Q: What about Alzheimer’s disease?

A: Prior to this point, no one has thought there was a connection between Fragile X syndrome and Alzheimer’s disease. One is a disorder children are born with and the other a disorder that affects people later in their lives. Researchers had never connected the two as having a common molecular pathway. Ongoing research in the Lombroso laboratory is testing the hypothesis that the protein STEP, that regulates glutamate receptor trafficking and removes them from synapses, is activated in both disorders.

Q: One would not normally think of schizophrenia when they think of learning and memory. What does your research have to do with the disorder?

A: A new area of research in the laboratory is in schizophrenia. A similar model is being tested in which STEP again is inappropriately expressed and leads to the cognitive deficits that afflict individuals with this devastating disorder. Current medications for the treatment of schizophrenia are much more effective for treating the positive symptoms and not very effective in treating the negative symptoms.

Q: What makes this research important?

A: The important implications of the work is developing medication that targets STEP, which may have important therapeutic benefits in several psychiatric disorders.

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