Glutamatergic regulation of cognition and functional brain connectivity: insights from pharmacological, genetic and translational schizophrenia research

The pharmacological modulation of glutamatergic neurotransmission to improve cognitive function has been a focus of intensive research, particularly in relation to the cognitive deficits seen in schizophrenia. Despite this effort, there has been little success in the clinical use of glutamatergic compounds as procognitive drugs. Here, we review a selection of the drugs used to modulate glutamatergic signalling and how they impact on cognitive function in rodents and humans. We highlight how glutamatergic dysfunction, and NMDA receptor hypofunction in particular, is a key mechanism contributing to the cognitive deficits observed in schizophrenia and outline some of the glutamatergic targets that have been tested as putative procognitive targets for this disorder. Using translational research in this area as a leading exemplar, namely, models of NMDA receptor hypofunction, we discuss how the study of functional brain network connectivity can provide new insight into how the glutamatergic system impacts on cognitive function. Future studies characterizing functional brain network connectivity will increase our understanding of how glutamatergic compounds regulate cognition and could contribute to the future success of glutamatergic drug validation.