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Psychiatry Newsletter - Schizophrenia: War to Save the Synapses
Schizophrenia: War to Save the Synapses
Date: November 29, 2010
The brain undergoes a massive overhaul in late adolescence—something that developmental biologists have long known and that teenagers, fortunately, can’t feel. In the late teens, there’s a grand pruning of “disposable” synapses, while Nature reinforces those she wants to keep.
The fact that schizophrenia symptoms surface at that same time of life has struck neuroscientists as no coincidence. Since the early 1990s, the idea’s been around that what trips the disease’s onset may be an overzealous reorganizing of critical synapses. And now, as better techniques add support to schizophrenia-as-a-synaptic-sickness, signs point to a revolution in the field.
We’ve asked psychiatrist/neuroscientist Akira Sawa, a key figure in the field, for some perspective. He also explains his thoughts—they approach optimism—that the brain might be salvaged from schizophrenia’s worst effects.
Q. There’s good evidence that both genes and environmental insults are at work in schizophrenia (SZ). And you’ve looked most, so far, at genes’ effects.
A. Yes. Though risk genes likely disturb how the brain develops in utero and just after birth, the minor abnormalities they create continue as the cortex ages. We think it possible, for example, that in the prodromal stage—before SZ’s full-blown onset—the very mild signs that people first show reflect an increasingly disturbed brain also undergoing natural synaptic remodeling. It’s not hard to believe such abnormal structure can then change a person’s thoughts and behavior!
Q. Many of your studies focus on DISC1—a mutant gene that did all but blow a trumpet to announce itself a decade ago as raising risk of the disease in a Scottish family. You’ve found firsthand how far-reaching that gene’s effects are.
A. DISC1 is far more important than we first realized. It plays a part in early growth of neurons, how they migrate in the brain, in the connections they make. Our lab has been following one DISC1 pathway, for example, that ends in forming synaptic spines important to learning and memory.
Q. You have a roadmap for your coming research with DISC1, but it looks more like a battle plan for you and Hopkins colleagues. War on schizophrenia.
A. I’m not married to DISC1. There are other genes too. But for now, it makes an excellent system to follow. We think at least four developmental pathways—birth through young adulthood—are differently touched by mutant DISC1. Someone needs to map each one; see what happens, see where it’s vulnerable to injury and, perhaps, to being made right.
Q. And then?
A. Ah.The most exciting part. Our lab believes those abnormal developmental routes merge to disturb a common pathway—one where glutamate-based conversations take place between inhibitory and excitatory neurons. It’s also the path most affected just before the onset of symptoms.
Q. Isn’t it also the target of PCP, the street drug that can make users psychotic and show other symptoms of schizophrenia?
A. Yes. Changes in this common path, we think, create the synaptic problems that underlie schizophrenia’s disordered behavior. And even slight adjustments to the path, with drugs, might offset the worst of the disease. Right now, we’re studying an agent in lab cultures that appears to right some of the wrongs.