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Fat Molecules Make Bigger Brains, Say Scientists at The Scripps Research Institute

La Jolla, CA. November 18, 2003 - A team of scientists at The Scripps Research Institute (TSRI) is publishing a study in an upcoming issue of the journal Nature Neuroscience that describes the effects of a particular phospholipid molecule on the development of mammalian brains.

Phospholipids, molecules of fat with a charged head on one end, are commonly found in biological organisms and are generally regarded as essential structural components of cells. Bilayers of phospholipids are the primary component of cellular membranes, for instance, those essential barriers that define the boundaries of cells and keep the molecules inside a cell separated from those outside a cell.

But lipids apparently do more than just form barriers.

In their study, the TSRI scientists examined the effect of molecules of a phospholipid called lysophosphatidic acid (LPA) on developing brains in murine models. They found that LPA can act as a signal that induces neurogenesis - the formation of new neurons. Previously scientists believed that growth factors and other proteins largely controlled neural development and neurogenesis.

"Fat [molecules] have new roles that we are only beginning to understand," says TSRI Professor Jerold Chun, M.D., Ph.D., who is an investigator in the Helen L. Dorris Child and Adolescent Neurological and Psychiatric Disorder Institute at TSRI. "They potentially have profound effects on brain development."

The work is significant because neural generation in early development predestines an organism for what happens later in life. The work may help clinicians and scientists understand some of the many diseases that arise from developmental defects that may be related to LPA signaling. Several childhood mental disorders and certain types of schizophrenia, for instance, are believed to be developmental in origin. The work may also help clinicians understand how to control stem cell differentiation - an important step for stem cell therapy.

A Wrinkle in Mind

Chun and his colleagues have been looking at what controls the formation of the cerebral cortex, the part of the brain that is believed to be involved in higher functions, like memory, cognition, and the interpretation of sensory input. The vast majority of these cerebral cortex neurons are generated before birth, and Chun and his colleagues, postdoctoral fellows Marcy Kingsbury and Stevens Rehen, along with graduate students James Contos and Christine Higgins, wanted to know what signals controlled this process in early development.

A few years ago, their study of LPA led them to identify the first cellular receptor to which it binds. Chun and his colleagues discovered that when LPA binds to this receptor in the embryonic brain, the result is a brain that shows a vastly increased number of neurons in the cerebral cortex.

Remarkably, LPA induces folds in the brain. When developing brains are exposed to LPA, the brains spontaneously form the gyrated structures that are characteristic of higher mammals, like humans. These gyrations increase the surface area of the cerebral cortex that is believed to be essential to higher functions like intelligence and reasoning, which are characteristic of humans and other primates. Such gyrations are not normally seen in the brains of lower mammals, like mice.

Interestingly, this neuronal increase works not by causing neuronal progenitor cells in the brain to proliferate and then become neurons, as one might expect, but by a new mechanism whereby the neuronal progenitor cells that normally would die are prevented from dying and other neuronal progenitor cells are forced to divide prematurely.

The article, "Enhanced Cerebral Cortical Growth and Folding by Non-Proliferative Effects Of Lysophosphatidic Acid" was authored by M. A. Kingsbury, S. K. Rehen, J. J. A. Contos, C. M. Higgins, and J. Chun and appears in the Advance Online Publication edition of the journal Nature Neuroscience on November 16, 2003. See: The article will appear in print later this year.

The work was supported by the Helen L. Dorris Child and Adolescent Neurological and Psychiatric Disorder Institute at TSRI and by grants from the National Institutes of Mental Health.

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