Creating Schizophrenic Mice, or, Infection and Insanity

Today's science question: how would you go about creating schizophrenic mice?

It's a trick question, actually, since mice can't get schizophrenia, and how would you know if they were having hallucinations anyway? But Urs Meyer, Swiss neuroscientist, and his colleagues think they have found mouse brain problems that are sort of analogous:

certain key cognitive deficits and behaviors can be measured in both animals and humans and are thought to rely on similar brain regions and neural circuits.

And once you think you can measure something like schizophrenia in mice, you can use them to test theories about the origin of schizophrenia. So how would you go about giving a mouse something analogous to schizophrenia?

Meyer wanted to test the old theory that schizophrenia actually requires two triggers: an infection early in life, or while in the womb, followed by some sort of severe psychological or physical stress in adolescence. The prenatal infection hypothesis was devised to explain some of the very weird facts about the incidence of schizophrenia, such as that it is more common in people born in the spring. That there is a connection of some kind now seems pretty well established. But, of course, most people exposed to prenatal influenza do not become schizophrenic. Hence the notion that there must also be a second trigger, something that happens later in life that bring to the fore what is only a potential problem:

In one group of mice, Meyer and his colleagues dosed their mothers with a synthetic compound that simulates a mild viral infection during late pregnancy; when their offspring hit early puberty at about 6 weeks of age, the young mice were exposed to unpredictable stress, such as being restrained, deprived of water, or given electric foot shocks. The second and third groups were exposed to infection or stress alone, while the fourth group grew up relatively unperturbed as a control. . . . the mice subjected to both prenatal infection and stress during puberty showed far greater behavioral deficits and cellular changes in brain regions relevant to schizophrenia than those that had been exposed to infection or stress alone. Rather than merely a cumulative effect, Meyer says, the two conditions appeared to act in synergy, increasing anxiety behaviors in the mice as well as damaging their performance on tests for associative memory and other basic cognitive skills associated in people with a range of neurological disorders, including schizophrenia.

One striking example, Meyer says, was a neurological test called prepulse inhibition (PPI) in which animals are startled by an unexpected noise such as an air horn. If they hear a quiet tone milliseconds before the blast, both mice and humans typically automatically diminish their startle response to a second, louder noise. When mice exposed to both infection and stress were tested for PPI, however, they responded to the second loud noise with the same intensity even if they had been exposed to a previous tone—the same deficit seen in humans with schizophrenia.

Differences can even be seen in the brains of the twice-tortured mice. So I would say this is quite a striking result, and pretty good evidence for the two-trigger theory of schizophrenia.

UPDATE: I told my teenage sons about this study, and they agreed that random electric shocks delivered by an invisible, monstrously evil being are a very good analogy for the stresses of adolescence.