Scientists have long eyed mutations in a gene known as DISC1 as a possible contributor to schizophrenia and mood disorders, including depression and bipolar disorder. Now, new research led by Johns Hopkins researchers suggests that perturbing this gene during prenatal periods, postnatal periods or both may have different effects in mice, leading to separate types of brain alterations and behaviors with resemblance to schizophrenia or mood disorders. Withdrawing doxycycline turned this gene on. When the mice were about 2 months old, the researchers put the animals through a battery of behavioral tests designed to measure characteristics similar to schizophrenia and depression in humans, such as abnormal social interactions and heightened aggression under stress, comparing these animals with "control" animals that didn't express the mutant gene.
Because previous studies have shown that male mice with mutant DISC1 have such altered traits, the researchers tested male mice in each of the groups by placing them in a cage with a normal male mouse and allowing them to mingle for 10 minutes. Pletnikov and his colleagues found that the Pre+Post and Post groups spent significantly less time in non-aggressive social interaction with their partners than the mice of the NO group. Those in the Pre+Post group also demonstrated significantly more aggressive attacks on their partners than control mice that did not express mutant DISC1. Mice thought to exhibit depression-like behavior spend more time immobile than non-depressed mice.
Pletnikov's team found that only female mice of the Post group spent significantly more time immobile in the forced swim test than mice that did not express mutant DISC1. Female mice in the Pre+Post group spent significantly more time immobile in the tail suspension test than control mice . Male mice in each of the groups displayed similar behavior in these tests.
Finally, when the researchers examined the brains of the mice, they found significant differences between animals in different groups. Those in the Pre group had significantly smaller brain volume than the other mice. Both female and male mice in the Pre, Post and Pre+Post groups had fewer neurons that produce GABA, a brain chemical that regulates nerve cell firing, than mice in the NO group.
While selective prenatal expression led to smaller brain volumes but mild behavioral effects, pre- and postnatal expression led to behaviors and brain alterations in male mice similar to schizophrenic humans, and postnatal expression produced abnormalities in female mice similar to depression.
The researchers aren't sure why the animals varied according to sex. However, Pletnikov notes, schizophrenia and depression also vary between the sexes in humans, with schizophrenia more prevalent in males and depression more prevalent in females. He and his team plan to study these sex-related differences in future studies.
Source
Johns Hopkins Medicine
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