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

Abstract

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.

The role of NMDA receptor antagonists, amantadine and memantine, in schizophrenia treatment: a systematic review

“…In the last years the understanding of glutamatergic pathways involvement in schizophrenia etiopathogenesis has advanced dramatically, especially after the implication that aberrant NMDAr functioning plays in this condition 4,19 . Therefore, the search for drugs that modulate these receptors activity could hypothetically bring benefits, especially with regard to cognitive symptoms 1,[5][6][7]10 . Although their mechanisms are not yet completely understood, amantadine and memantine are very interesting drugs because their ability to antagonize NMDAr and promoting a regulation in this pathological receptor activity without compromising the physiological action 22 .…”

“…As a main excitatory neurotransmitter, glutamate performs several functions in human brain such as attention 5 , memory and cognition processes 6,7 . Nevertheless, high glutamate levels overactive their receptors inducing neuronal damage, a process known as excitotoxicity, due to high calcium influx 8 .…”

“…When this receptor is activated, a signal transduction cascade starts resulting various changes inside the neuron. Others receptors, such as a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAr), kainate and NMDAr, are classified as ionotropic receptors, i.e., a receptor linked to an ionic channel 6,9 .…”

Modulation on Glutamic Pathway of Frontal-Striatum-Thalamus by rs11146020 and rs3813296 Gene Polymorphism in First-Episode Negative Schizophrenia

“…Several SNPs have been associated with increased risk for developing schizophrenia, although few of these findings have been replicated (Jagannath et al, 2018). If confirmed in additional studies, these genetic markers would implicate glutamatergic neurotransmitter pathways in the pathogenesis of schizophrenia (Dauvermann et al, 2017;Saini et al, 2017;Han et al, 2018).…”

Pharmacology of cognition: a panacea for neuropsychiatric disease?

“…Dauvermann et al . () review how advances in neuroimaging and genetic research have furthered our understanding of the specific brain circuitries that underlie cognitive processes. These authors focus on the role of glutamatergic systems, and NMDA receptor hypofunction in particular, in the cognitive deficits observed in schizophrenia.…”