Although mental illnesses are primarily considered human disorders, investigators have attempted to model certain aspects of these disorders in animals to facilitate study of the underlying mechanisms. In such studies, researchers have noted that gene mutations can elicit certain abnormal behaviors in rodents that are very similar to isolated symptoms of mental illness in humans. These behaviors are called endophenotypes.

Mutation of proteins that make up the postsynaptic density (PSD), a protein complex located at the 'receiving' end of a synapse or electrochemical connection between neurons, have been associated with cognitive defects and mental illnesses in humans. Similarly, mutations in PSD proteins in rodents can produce endophenotypes of mental illnesses. In a recent example, scientists from California Institute of Technology (Pasadena) and University of California, Los Angeles, describe endophenotypes of schizophrenia and autism spectrum disorders associated with null mutations of the gene encoding PSD protein densin-180 in mice.

Compared with normal mice, mice lacking densin-180 had deficits in hippocampus-dependent and -independent short-term memory, in prepulse inhibition, used as a measure of the ability to filter sensory information, and in nesting behavior (J. Neurosci. 31, 16194–16207; 2011). They also showed hyperactivity in response to stress and novelty, as well as abnormal aggression and anxiety behaviors. These defects are considered endophenotypes related to human mental illness. “Studies of mice with schizophrenia and autism-like features have reported similar behaviors,” noted Mary B. Kennedy, who led the study, in a press release.

The densin-180 knockout mice also had lower amounts of other PSD proteins. Kennedy explained that “densin-180 helps to hold together a key piece of regulatory machinery in the postsynaptic part of excitatory brain synapses.” Densin-180 functions as a scaffold in the PSD, influencing organization and signaling within the complex. This organizational role means that densin-180 influences multiple cellular functions; hence, the lack of densin-180 leads to complex behavioral phenotypes.

The study results are consistent with the hypothesis that genetic mutations that disrupt postsynaptic signaling at excitatory synapses can cause behavioral endophenotypes of mental illness. “We don't know precisely how the molecular defect leads to the behavioral endophenotypes. That will be our work going forward,” Kennedy said. “The molecular mechanistic links between a gene defect and defective behavior are complicated and, as yet, mostly unknown. Understanding them goes to the very heart of understanding brain function.”