Salk Institute for Biological Studies


Stephen F. Heinemann

Stephen F. Heinemann

Molecular Neurobiology Laboratory



Stephen F. Heinemann, a professor in the Molecular Neurobiology Laboratory, studies the molecular details of communication among brain cells. The synapse plays a key role in communicating information between brain cells and it is likely that biochemical changes at the synapse underlie some aspects of higher brain function. Most plausible theories of learning and memory depend upon changes in the efficiency of chemical synapses, which probably involves changes in receptors, ion channels and neurotransmitter release. It is also now known that these molecules can be directly involved in human disease. Most drugs that are used to treat mental illness are known to work either on the receptors or the metabolism of the transmitters at the synapse. The work in the laboratory is focused on the molecular biology and physiology of the glutamate and nicotinic receptors expressed in the brain. A major goal is to understand the regulation of synaptic function and the molecular biology of learning.

Among other notable achievements, his lab has isolated a gene containing the blueprints for a receptor critical to learning and memory, and identified the receptors that respond to nicotine. Since neurological ailments, such as Alzheimer's and Parkinson's; drug addiction; and mental disorders, such as depression and schizophrenia, are fundamentally disorders of brain cell communication, this research will provide new insights into the treatment of these disorders. Discoveries in Heinemann's lab are currently being used by pharmaceutical and biotechnology companies to develop drugs for stroke, epilepsy, Parkinson's and Alzheimer's diseases, as well as mental conditions, such as nicotine addiction, depression and schizophrenia.

"The work in our laboratory is focused on the molecular mechanism by which nerve cells communicate with each other at specialized connections, or synapses. Recent work in the laboratory has supported the idea that many diseases of the brain result from deficits in communication between nerve cells or synapses."

For close to a decade, pharmaceutical researchers have been pursuing compounds to activate a key nicotine receptor that plays a role in cognitive processes. Triggering it, they hope, might prevent or even reverse the devastation wrought by Alzheimer's disease. Researchers in Heinemann's lab, however, whose group first identified the brain receptors that respond to nicotine, have discovered that when the receptor, alpha-7, encounters beta amyloid, the toxic protein found in the disease's hallmark plaques, the two may actually go rogue. In combination, alpha-7 and beta amyloid appear to exacerbate Alzheimer's symptoms, while eliminating alpha-7 seems to nullify beta amyloid's harmful effects.

Alpha-7 is expressed all over the brain, in all mammals, which means that it is probably essential, but investigators have not yet discovered for what. Intrigued by earlier studies showing that beta amyloid seemed particularly drawn to the alpha-7 nicotinic receptors, Heinemann and his team hypothesized that the receptors mediate beta amyloid effects in Alzheimer's disease. To test their theory, they crossed mice engineered to lack the gene for alpha-7 with a mouse model for Alzheimer's disease, which had been genetically engineered to overexpress amyloid precursor protein (APP), an antecedent to beta amyloid. They then put the offspring through a series of memory tests. Surprisingly, those with both mutations—too much APP and no gene for alpha-7—performed as well as normal mice. The Alzheimer's mice, however, which had the alpha-7 gene and also overexpressed APP, did poorly on the tests. Pathology studies revealed the presence of comparable amounts of plaque in the brains of both types of mice, but in those lacking the alpha-7 gene, they appeared to have no effect. Similar disparities were evident in measurements of the synaptic function underlying learning and memory.

These findings, which suggest a completely different target for potential Alzheimer's drugs than those that have been tried, could have important implications for researchers seeking to combat the disease.

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