Symptoms in Mice Lacking a Single Receptor Type Mimic the Development of Schizophrenia
Deleting one type of neurotransmitter receptor in a specific population of brain cells can induce schizophrenia-like behavior in mice, but only when the receptor is deleted early in development, according to a study by NIMH intramural scientists. The work provides strong support for previous observations implicating these receptors in psychosis; further, the mice provide a model of how psychotic symptoms can arise from a disruption in neuronal development, consistent with observations of how schizophrenia emerges in humans.
Glutamate is the brain's chief excitatory signaling molecule, or neurotransmitter, lowering the threshold at which neurons will fire and send a signal to adjacent neurons. Past studies have shown that drugs that shut down a specific type of receptor for glutamate—the NMDA receptor (NMDAR)—cause psychotic symptoms that resemble schizophrenia. That observation has led to a theory that psychosis in schizophrenia can be traced to reduced NMDAR function. Past work has also implicated a specific population of cells—interneurons—in schizophrenia. Interneurons function as integrating connectors between other neurons. Signaling by interneurons characteristically involves the inhibitory neurotransmitter GABA, which, contrary to glutamate, acts to slow the pace of neuronal activity.
To explore whether reduced NMDAR function in interneurons could cause psychosis, scientists in NIMH's intramural program, led by Dr. Kazu Nakazawa, used a technique that allowed them to create mouse lines in which an essential subunit of the NMDA receptor was deleted ("knocked out"), but only in interneurons in areas of the brain (the cortex and hippocampus) that are thought to be particular targets of reduced NMDAR function. The method they used allowed them to create mouse lines in which they could vary the timing of the deletion: in one mouse line, the deletion was evident early in postnatal development; in the other, the deletion took place after the mice had reached adulthood.
By four weeks of age, a time period that corresponds roughly to infancy in humans, NMDA receptors were knocked out in one of the mouse lines. After a delay of several weeks, testing showed a number of types of behaviors analogous to schizophrenia in humans. As in humans, there was a latency, or prodromal period, before signs of abnormal behavior became apparent.
In tests of exploratory behavior, the knockout mice showed signs of hyper-reactivity and increased anxiety. They also showed reduced appetite for sweet solutions and deficits in nesting and mating, all signs that parallel the negative symptoms seen in schizophrenia: a lack of pleasure in everyday activities, and a reduced ability to plan and carry out tasks. Social and working memory were also affected in the mice. In another parallel to human schizophrenia, symptoms showed up earlier in mice that had been raised for several weeks in isolation, a form of social stress. Finally, no symptoms appeared in mice in which the NMDA receptors were knocked out after 12 weeks.
In this study, reduced function of NMDA receptors in a specific population of cells was sufficient to cause symptoms resembling schizophrenia in humans, providing the first direct evidence that these cell receptors are central in the origin of psychosis. The fact that the symptoms developed over time, and only when the receptors were deleted in younger mice, also depicts a process consistent with the view of schizophrenia as a disease in which a failure in one type of neuronal signaling throws off the normal formation of neuronal connections (synapses) and leads to disease.
This knockout mouse provides a model for exploring the role of NMDA receptors in schizophrenia. Future studies will address what could cause reduced NMDAR function in people with schizophrenia; how disrupted regulation of this receptor causes symptoms and how stress exacerbates them; and how currently-used medications work to alleviate symptoms. Ultimately, understanding these processes will provide the basis for developing new, targeted medications.
A provocative aspect of these results is that deleting the receptor in adult mice failed to cause symptoms, a surprise given the fact that drugs with an analogous effect on the receptor cause symptoms in adult humans and animals. A question for future research is whether the drugs that target NMDA receptors also have broader actions that explain their ability to cause psychosis. In addition, the study found that deleting a receptor for glutamate—which is excitatory—resulted in increased, not decreased, activity of neurons in the cortex. The explanation may be related to regulation by glutamate of interneuron activity, which is in turn GABA-based and inhibitory.
Belforte, J.E., Zsiros, V., Sklar, E.R., Jiang, Z., Yu, G., Li, Y., Quinlan, E.M. and Nakazawa, K. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nature Neuroscience published online 11/15/2009; doi: 10.1038/nn.2447