By David N. Leff

Much of the world's finest cut-glass crystal comes from Central Europe. Its production there is as much art as industry.

Picture a vast hall filled with dozens of stands holding the smooth glass goblets, bowls and other freshly cast workpieces, waiting to be cut, ground and polished. In front of each upright stanchion stands a skilled artisan, wielding what looks like a diamond-tipped dentist's drill.

The high-pitched screeching, shrieking, whining sound they generate is as unbearable as fingernails scratching a chalk board * but amplified to ear-splitting agony.

Yet loudspeakers fill the hall with the soothing strains of background music.

The tour guide explains that the workers hear and appreciate this melodic input, because their ears are habituated to filter out the high-frequency noise of their drills.

Such auditory filtering is what makes life bearable for all of us. It enables people to converse amid the noise of traffic, for example. And the absence of that ability to damp down background noises makes life less bearable for the 15 people in a thousand who are afflicted with schizophrenia. (See BioWorld Today, Aug. 15, 1995, p. 1.)

Of course, auditory filtering deficit is only one of the many hallmarks that define schizophrenia. Hallucinations, delusions, social withdrawal, thought disorder, are the main diagnostic symptoms that mark the disease. But the auditory shortcoming is a trait that can be quantified in schizophrenics, because its cause is physiological, rather than "in the mind."

That filter rises in the nerves of the brain's auditory nuclei, and flows to the hippocampus and cerebral cortex.

"As a matter of fact," said psychiatrist and neurophysiologist Robert Freedman, "we and others think that the filtering phenomenon is a manifestation of the same kind of brain abnormality that gives rise to schizophrenic hallucinations, delusions and attentional disorders. We're just seeing it at a neuronal level," he told BioWorld Today.

"Schizophrenics often pay attention to apparently extraneous auditory stimuli in their surroundings that normal individuals generally ignore," Freedman observed. "And patients tell us that they have difficulty concentrating, particularly in environments where there's a great deal of such stimulation."

Freedman, who teaches and practices at the University of Colorado School of Medicine, in Denver, is first author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated Jan. 21, 1997. Its title: "Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus."

He and his co-authors report studying that inherited deficiency of auditory filtering in the brains of rats, and in the genomes of families with schizophrenic members.

"The purpose of our rat experiments," Freedman said, "was to determine as best we could what all the different neurotransmitters involved in this particular trait might be."

The group subjected the animal models to a succession of auditory clicks * electronic pulses * at half-second intervals, then recorded their responses at the level of individual neurons firing.

"We encountered responses all through the rat brain," Freedman said, " but we found that the critical area for determining an animal's ability to diminish its responses to the repeated stimuli was in pyramidal neurons of the hippocampus. There, the critical thing that was happening was cholinergic stimulation of the nicotinic cholinergic receptor."

Nicotine's Neuronal Connection

That receptor, he explained, is for acetylcholine, but this nicotinic receptor variant, alpha-7, mimics the effects of that mainline neurotransmitter, which is why schizophrenics are well-known to be heavy chain-smokers.

"We know that when schizophrenics smoke," Freedman continued, "they normalize this deficit in sensory filtering. We measure that effect of nicotine on brain activity, using evoked potentials * electroencephalogram waves. Patients report that they feel a greater ability to concentrate."

However, the effect at the receptor is only transient, so they smoke virtually non-stop.

In consequence, Freedman pointed out, "Schizophrenics have a lot of lung cancer and heart disease." Surrogate nicotine fixes, via chewing gum or transdermal patches, he said, "don't give a high enough dose of nicotine to be effective, and in addition the long-term exposure to the drug probably causes some nicotinic receptor desensitization.

"Because we were interested in this receptor," Freedman went on, "we isolated the gene for it in a yeast artificial chromosome [YAC], and then looked for repeated CA [cytosine-adenine] nucleotide sequences. These CA repeats," he pointed out, "are the most common polymorphism in the human genome."

He and his team tracked that alpha-7 nicotinic receptor gene, with its CA mutation, to the long arm of human chromosome 15.

In nine extended families with 104 members, 36 of them diagnosed schizophrenics, the team performed auditory click response testing, and linkage analysis for the dinucleotide CA polymorphism.

All subjects had previously given written consent to participate in these experiments. Freedman observed that "Schizophrenics are generally considered competent to give informed consent. They have normal intellectual capabilities.

"Our finding," he summed up, "was that there was a significant association between the CA polymorphism that we had isolated from the genome at the site of the alpha-7 nicotinic receptor and the autosomal dominant inheritance of the filtering abnormality."

Interestingly, normal as well as schizophrenic family members inherited the auditory-deficit trait, for which both groups are heterozygotic. What accounts for this seeming anomaly, Freedman said, "we don't know for sure. However, we have done some magnetic resonance imaging studies of schizophrenic brains compared to those of their siblings who have only the filtering deficit. In general, the schizophrenic people have smaller hippocampi.

"One suggested explanation," he added, "is that with the filtering deficit, if your brain is otherwise pretty normal, then you won't get schizophrenia. But if you have some other additional abnormalities that cause a fewer number of neurons to develop, then the inability to filter becomes disastrous in developing schizophrenia."

Freedman observed that the study reported in PNAS "is the first time that a specific physiological deficit in schizophrenia has been linked to a gene that appears to have a known function in that deficit. So it links the physiology of schizophrenia with its genetics."

From Gene Discovery To Drug Discovery

His laboratory "is now trying, as its major effort, to sequence the mutation that gave rise to this linkage signal. That will tell us a lot more about how the gene is functioning in schizophrenia."

He suggests that this line of research may have an impact on discovering new drugs to treat schizophrenia. "We think that there is a role for an agonist to the nicotinic receptor," he said. "Clozapine, which is the most promising of the new neuroleptic drugs, does normalize this auditory potential. And we don't know its mode of action yet."

Freedman and his group are "in touch with some pharmaceutical companies, trying to entice them to get interested in this particular physiology, with the hope that we can direct a better treatment towards it than nicotine." *