In 2000, Japanese researchers discovered a family of three receptors that exist in very similar form in the brain cells of all vertebrates. The fact that evolution had conserved them so strongly hinted, in the words of the researchers, at “the existence of undiscovered fundamental neuronal systems” involving these receptors. The researchers dubbed them Superconserved Receptors Expressed in Brain, or SREB.
SREB2, found on chromosome 7, turned out to be the most highly conserved of all three, and the most highly conserved receptor of its kind in humans. The gene for SREB2 in humans was determined to be essentially identical to that found in mice and rats, and 94 percent similar to the SREB2 gene in zebra fish.
But despite years of subsequent investigation, SREB2’s normal functions remained unclear. Now its Japanese discoverers, working with American researchers from the National Institute of Mental Health (NIMH), report that abnormalities of SREB2 affect brain size and behavior and appear to be associated with a higher risk of schizophrenia.
Led by Mitsuyuki Matsumoto from Astellas Pharmaceuticals, the researchers created transgenic lab mice with double the normal expression of the SREB2 gene in the cerebral cortex and hippocampus—a mild overexpression by transgene standards. As they reported in the April 22 issue of the Proceedings of the National Academy of Sciences, the neurons that grew in these areas were smaller and developed fewer connections in the weeks after birth.
Apparently as a result, more of these neurons died during the developing brain’s automatic winnowing-out process, and the brains of these mice as adults weighed about 20 percent less than normal. Behavior changes suggested social withdrawal, problems with sensing and reacting to stimuli, and memory deficits—all reminiscent of the abnormalities seen in people with psychiatric disorders.
When the researchers checked a National Institutes of Health database that held genetic details on more than 250 people with schizophrenia and their family members, they found that those with the disorder were significantly more likely to have one of several rare SREB2 variations.
Daniel Weinberger, a contributor to the study and the director of the Genes, Cognition and Psychosis program at NIMH, says that since submitting the PNAS paper, “We’ve done a lot more work in looking at genetic variation in normal people and how it affects various aspects of memory or other brain functions, and we’re increasingly showing, as we showed in this paper, that variations in this [SREB2] gene affect aspects of normal brain function. So we’re generally moving in the right direction.”
In particular, Weinberger notes, the specific variations in SREB2 associated with schizophrenia appear to affect brain functions normally altered in the disorder, including “aspects of hippocampal function related to memory, and frontal function related to attention.”
The SREB receptors belong to the well-studied G-protein-coupled receptor class—“the classic target for the development of a neuropharmacological agent,” says Weinberger. In fact, close to half of all pharmaceuticals today target G-protein-coupled receptors.
“They mediate a wide-variety of physiological functions,” says Adriano Marchese, a pharmacologist at Loyola University of Chicago who has authored review papers on the subject. “These functions include neurotransmission, heart rate control, blood pressure, pain perception, cell proliferation and growth, the sense of taste and smell, and vision.”
Based on the finding that too much SREB2 activity seems to be harmful to the brain, Weinberger’s Japanese colleagues are working to develop a SREB2 antagonist to reduce the receptor’s activity. The receptor may be of such importance in the signaling pathways of the brain, says Weinberger, that a drug to modulate its activity could benefit many people, “even if they don’t have a genetic abnormality in this particular gene.”
But mysteries about SREB2 remain. The “natural ligand,” the molecule in the brain that normally binds to SREB2, has not yet been found. (“It’s a matter of screening a lot of different molecules,” notes Weinberger.)
Even more mysterious is the effect seen when mice are bred to lack the SREB2 gene entirely. As described in the PNAS paper, the researchers expected such “knockout mice” to die in infancy. Instead they grew to have brains that were about 10 percent larger than normal and showed moderately better memory capabilities in a fear-stimulus test.
The researchers still don’t understand how a gene that evolution has treated with such importance could be knocked out with such moderate and apparently even beneficial effects. Weinberger suggests that for much of its history it might have had other roles outside the nervous system. “So it might be highly conserved because [mutations] would be lethal in some other context that we’re not studying in these particular animals,” he says.
Weinberger and his colleagues plan to present more data on SREB2 at the Society for Neuroscience conference in November.