Scientists at the Medical College of Georgia (MCG) believe that they have created a schizophrenic mouse model. They did this by reducing the inhibition of brain cells involved in complex reasoning and decisions about appropriate social behavior.
The research, published December 28 in Proceedings of the National Academy of Sciences, elucidates the critical balance between excitation and inhibition of these cells, which appears to go awry in schizophrenia.
The researchers made the mice by deleting a candidate gene for schizophrenia, ErbB4, from interneurons, which are brain cells that help shower larger decision-making neurons called pyramidal cells. Previous studies by the MCG team found how ErbB4 and another gene called neuregulin-1 work together to balance the activity of these pyramidal cells.
They reported in Neuron in May 2007 that the two help keep a healthy balance between excitation and inhibition by increasing release of GABA, a major inhibitory neurotransmitter, in the inhibitory synapses of the brain's prefrontal cortex. Seven years earlier, they showed the two also put a damper on excitatory synapses.
In the most recent research, they altered the natural checks and balances in cells directly involved with supplying pyramidal neurons. They did this by knocking out the ErbB4 gene in nearby chandelier and basket interneurons that supply GABA to pyramidal cells. “If we take out ErbB4 in these two interneurons, the neuregulin should have no effect because it can't promote GABA,” explains Lin Mei, M.D., Ph.D., Georgia research alliance eminent scholar in neuroscience.
His postulation played out in the behavior of the mouse, who exhibited schizophrenia-like behavior including increased movement and impaired short-term memory, according to the MCG investigators. The team is still gathering data on the manic aspect of schizophrenia in their mice.
For example, both the normal and knockout mice learned they would find a food pellet in each arm of an eight-armed chamber but that if they went to the same arm for seconds, there were none. But the knockouts took longer to learn and finish the task. Knockouts also spent a lot more time sniffing, snooping around, and revisiting empty arms.
In another test, knockouts couldn't make the connection that a relatively low noise would be followed by a slightly louder one. When they treated the knockouts with diazepam, an antianxiety medication, they responded similarly to the normal mice: the first sound prepared them for the second.
Dr. Mei suspects that if he could look at the chandelier and basket interneurons in the prefrontal cortex of schizophrenics, he would also find something wrong with their usual role of sensing the need for the inhibitor GABA and supplying it to the pyramidal cells. “In schizophrenia, the baseline of the excitatory neurotransmitter is probably high,” he notes.