Drug development: The modelling challenge

When Patricio O’Donnell started his lab in 1997 at Albany Medical College in New York, schizophrenia research seemed to be moving forward after a long period of stagnation.
For several decades, attention had focused on the idea that the disease was caused by elevated dopamine levels in the brain, particularly in the striatum, a nugget of brain tissue nestled under the cortex. But by the 1990s, the dopamine hypothesis was proving inadequate to fully explain the disease. In vivo imaging with computed tomography and magnetic resonance imaging, and data from post-mortem studies in people with schizophrenia, pointed to cortical effects and implicated other neurotransmitter systems, such as glutamate and serotonin. Biologists were also learning to create transgenic mouse models of the disease, providing a set of tools with which to investigate genetic and aetiological factors.

This proliferation of ideas opened the doors to fresh avenues of investigation, as well as new ways of modelling the disease in animals. The classical rodent model for schizophrenia had involved administering amphetamine — which ramps up dopamine levels in synapses and can cause hallucinations and delusions in people — and then measuring behaviours such as hyperactivity or passive avoidance. Researchers then began using other pharmacological agents, such as phencyclidine (PCP) and ketamine, which interfere with the glutamate receptor NMDA, or knocking out specific genes, such as those that code for neurotransmitter receptors.

O’Donnell was captivated by one particular approach that entails chemically damaging part of the hippocampus in newborn animals. Rodent pups who receive this intervention initially appear normal, but they later become socially withdrawn and overly responsive to stress, and their cortices show some of the physiological changes observed in post-mortem tissue. These findings reflect the now-accepted hypothesis that schizophrenia is a developmental disorder. “What made it attractive to me was that even though the lesion was done really early in development, all these behavioural abnormalities didn’t emerge until adolescence,” says O’Donnell, now vice-president and head of psychiatry and behavioural disorders at Pfizer Neuroscience in Cambridge, Massachusetts.

Attempts to mimic the symptoms or underlying physiological effects of schizophrenia have multiplied since then. As genome-wide association studies began pinpointing genes associated with the disease (see ‘Unravelling complexity’, page S6), researchers have knocked out or perturbed those genes in mice. Others have looked at environmental stressors, such as prenatal infections, early social isolation or stress, or lesions, like the ones O’Donnell used in the hypothalamus. And others give animals drugs such as amphetamine, ketamine and PCP. Some researchers have begun combining some of these manipulations — delivering an environmental stressor, for example, to mice lacking a particular schizophrenia-associated gene.

But when it comes to developing drugs, which are the best models? “