Memory, Pain, Depression, and Peptides... Putting the Pieces Together

By Jason Socrates Bardi

Sometimes the greatest moments in one's professional career are those in which one's accomplishments are not recognized.

Such a moment occurred for Tamas Bartfai in 1983, when he wrote a paper together with Tomas Hokfelt and Jan Lundberg claiming that he had identified a neuron that used not just one, but two neurotransmitters. They had discovered, in these neurons, the coexistence of the acetylcholine (ACH) and vasoactive intestinal polypeptide (VIP), two molecules that are released into synapses and transmit nerve impulses—a coexistence that was not thought possible at the time.

His manuscript was less than well received.

"We were rejected from every major journal," says Bartfai, who is professor of neuropharmacology and director of the Harold L. Dorris Neurological Research Center at The Scripps Research Institute (TSRI). "'It is well known that a neuron can have only one transmitter or we would have cacophony in the brain,' wrote one Nobel laurate referee."

Today there are over 40 well-documented examples of neurons with coexisting neutotransmitters. These examples have been described in thousands of papers, and more are discovered every year.

"I am quite pleased when I look at that paper rejected by Nature," he says.

What's in a Brain

Bartfai describes himself as a molecular neurobiologist—someone who attempts to associate cellular and molecular mechanisms to the phenomenon of cognition. Bartfai's own interests involve specifically identifying the molecular correlates of changes in long-term memory and in emotional states.

These attempts are, by Bartfai's own admission, mere starting points. Cognition is a complicated subject from a molecular perspective due to the number of neurons, neurotransmitters, and interconnections. There are emotional components, attentional components, sensory inputs, the creation and retention of short- and long-term memory, and the molecular interactions between these disparate events. There are stimuli and signals to be sorted out, and different regions of the brain that are involved in the different types of memory.

"We think in terms of very few transmitters and very few neurons and very few connectivities when we imagine how all of this works as compared to the trillions of nerve cells that actually participate," says Bartfai. "Where are these proteins formed, and are they specific to memory or to a circuit? What are the rules for reading them out when you recall a memory?"

"These are things that we don't really know much about," he says.

Understanding the connection between cellular and molecular interactions and cognition is one of Bartfai's key goals, but he also wants to find ways of turning these basic observations into useful therapeutics—therapeutics to counter degenerative diseases like Alzheimer's disease, which is characterized by a loss of memory.

Long-term memory involves the synthesis of new proteins, a characteristic that makes it amenable to someone like Bartfai, who is a biochemist by training. Because new proteins are formed as memories are formed, proteins and memories could, in theory, be alternatively blocked by synthesis inhibitors or enhanced by regulating the production of those inhibitors.

But, says Bartfai, at the moment, we are only really good at identifying non-specific ways of impairing memory, such as through alcohol. There are no drugs proven to enhance human cognitive ability or to help bring damaged cognition back to a more normal state.

"To stop the decline of memory," says Bartfai. "That is what we are really talking about—not making super IQ's, because there are enough of those already."

Unveiling the Effects of Peptides

One of the systems on which Bartfai is working is neurons that, like those he identified in 1983, use two distinct neurotransmitters. These are the cholinergic neurons that project to the hippocampus, and he is actively pursuing them because they are concentrated in a locus—called the Nucleus Basalis—which provides acetylcholine input to the hippocampus, is important for cognition, and which is severely damaged in Alzheimer's disease.

The hippocampus is a ridge of tissue along the lateral ventrals of the brain sandwiched between the cerebral cortex and the thalamus. This is where we think many of the chemical processes take place that are important for forming and retaining memories, the basic processes of cognition.

Cholinergic inputs to the hippocampus contain both the neurotransmitter acetylcholine (ACh) and the neuropeptide galanin. These two chemicals coexist specifically in those hippocampus neurons, and both chemicals are released into the gaps, or synapses, between two neurons during the signaling from one neuron to another that takes place during cognitive processes.

Acetylcholine is a well characterized neurotransmitter and one with which Bartfai is very familiar. In the early 1970s, simultaneous with S.H. Snyder and Sir Arnold Burgen, he made the first identification of muscarinic ACh receptors in the brain, which are one type of neuronal receptors for acetylcholine, and his research in this area has continued since then.

"In the end," says Bartfai, "everything we do in my laboratory turns out to have to do with modifying the cholinergic activity in the brain."


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Tamas Bartfai is professor of neuropharmacology and director of the Harold L. Dorris Neurological Research Center.