Using Nonhuman Primate Models to Reverse-Engineer Prefrontal Circuit Failure Underlying Cognitive Deficits in Schizophrenia.

In this chapter, I review studies in nonhuman primates that emulate the circuit failure in prefrontal cortex responsible for working memory and cognitive control deficits in schizophrenia. These studies have characterized how synaptic malfunction, typically induced by blockade of NMDAR, disrupts neural function and computation in prefrontal networks to explain errors in cognitive tasks that are seen in schizophrenia. This work is finding causal relationships between pathogenic events of relevance to schizophrenia at vastly different levels of scale, from synapses, to neurons, local, circuits, distributed networks, computation, and behavior. Pharmacological manipulation, the dominant approach in primate models, has limited construct validity for schizophrenia pathogenesis, as the disease results from a complex interplay between environmental, developmental, and genetic factors. Genetic manipulation replicating schizophrenia risk is more advanced in rodent models. Nonetheless, gene manipulation in nonhuman primates is rapidly advancing, and primate developmental models have been established. Integration of large scale neural recording, genetic manipulation, and computational modeling in nonhuman primates holds considerable potential to provide a crucial schizophrenia model moving forward. Data generated by this approach is likely to fill several crucial gaps in our understanding of the causal sequence leading to schizophrenia in humans. This causal chain presents a vexing problem largely because it requires understanding how events at very different levels of scale relate to one another, from genes to circuits to cognition to social interactions. Nonhuman primate models excel here. They optimally enable discovery of causal relationships across levels of scale in the brain that are relevant to cognitive deficits in schizophrenia. The mechanistic understanding of prefrontal circuit failure they promise to provide may point the way to more effective therapeutic interventions to restore function to prefrontal networks in the disease.