Schizophrenia is one of psychiatry's most puzzling afflictions, with a complex of symptoms that goes far beyond its hallmark hallucinations and delusional thinking. But new research has found connections among several of schizophrenia's peculiar collection of symptoms -- including agitation and memory problems -- and linked them to a single genetic variant among the hundreds thought to heighten risk of the disorder.
The findings offer new insights into the molecular basis for schizophrenia and could lead to treatments for the disease that are more targeted and more comprehensive.
Published Monday in the journal Nature Neuroscience, the study looks at how a gene variant called Arp2/3 contributes to psychosis, agitation and problems of short- and long-term memory. Mice that were genetically modified to lack the Arp2/3 gene variant showed all three symptoms (although to measure psychosis in mice, scientists looked instead for an abnormal startle response that is also seen in humans in the grips of psychosis).
The study's authors, led by Duke University neurobiologist Scott Soderling, then dug below those behaviors to see whether brain abnormalities linked to such behaviors had anything in common. Mice that lacked the Arp2/3 gene variant, they discovered, had not only symptoms of schizophrenia, but also several of the underlying brain abnormalities most closely linked to psychosis, agitation and memory problems seen in those with schizophrenia.
In the deep recesses of a schizophrenia patient's brain, outward manifestations such as delusional thinking and cognitive problems are thought to have their origins in brain cells that look and act differently than they should. Researchers have long puzzled over three seemingly unrelated brain abnormalities in schizophrenia.
-- First, the cells of the brain's frontal cortex -- the seat of planning and decision-making -- have fewer than normal "dendritic spines," the projecting branches that reach out from one neuron to another to form connections.
-- Second, in the same region, opposing types of brain cells -- excitatory and inhibitory -- are supposed to fire in balance. But in schizophrenia, the excitatory neurons are overactive.
-- Third, those with schizophrenia routinely have too much of the neurotransmitter dopamine in the striatum, a region of the brain that is key to initiating and performing movement.
After knocking out Arp2/3, the Duke neuroscientists watched in surprise as the brain cells of mice wired themselves to go around the stunted or missing dendritic spines. When they did so, however, those brain cells bypassed a filter that usually keeps excitatory impulses in check. Result: overexcited excitatory neurons.
In mice, the effects was degraded performance on tests of short- and long-term memory.
To the researchers' further surprise, those hyperactive brain cells sent a frenzy of electrical signals into the brain's ventral tegmental area -- a region that's key to cognition and to motivation and that is a wellspring of dopamine. Their order to neurons there: dump large volumes of dopamine.
"That was really cool for us, when these three pieces of the puzzle fell together," said Soderling. "Because this is a big puzzle."
The antipsychotic medication haloperidol, marketed as Haldol, has long worked to tame schizophrenia symptoms by reducing the amount of dopamine in the brain. But Soderling said it now appears that too much dopamine is the result of a cascade of misfirings, and not the root of the problem.
That insight, he said, may offer researchers better ways to interrupt schizophrenia's molecular cascade of errors before it results in a host of disabling psychiatric symptoms.
But while they have reconciled three once-distinct theories of schizophrenia's cause, Soderling and his colleagues have only begun to unravel the secrets of the disorder. What error in cells and circuitry underlie other hallmark symptoms of schizophrenia, such as lack of motivation and difficulty in reading and acting on social cues? Soderling said he hopes future experiments in which the function of genes, including Arp2/3, are deleted and restored, will begin to provide answers.