Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

Abstract

Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post‐mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.

scGRNom: a computational pipeline of integrative multi-omics analyses for predicting cell-type disease genes and regulatory networks

“…From the inhibitory neuron standpoint, SCZ enrichment shared multiple enrichment terms with AD, suggesting abstraction from standard disease-specific pathology and broader atypical neuronal signaling and activity. Specifically, we observed MAPK family signaling (p<1.63e-9) [42], regulation of NMDA receptor activity (p<5.09e-8) [56], dopaminergic synapses (p<2.07e-7) [40,41], and neurotransmitter-based signal transmission (p<3.71e-18) [56] to be enriched. The general consensus is that similar pathways are observed to be enriched between diseases and cell types, but there are disease and cell type specific implications for clinical presentation.…”

“…Lastly, SCZ enrichment for both excitatory and inhibitory neurons were similar to those of AD, possessing unique, diseasespecific interactions. For excitatory neurons, we observed neurotransmitter-based signal transmission (p<1.11e-13) [56] as well as regulation of trans-synaptic signaling (p<1.46e-29) [45], synapse structure and activity (p<1.02e-15) [49], and glutamate receptor signaling (p<3.90e-12) [41]. From the inhibitory neuron standpoint, SCZ enrichment shared multiple enrichment terms with AD, suggesting abstraction from standard disease-specific pathology and broader atypical neuronal signaling and activity.…”

“…This is vital to the understanding of a multitude of diseases that commonly demonstrate atrophy of cortical tissue as a hallmark feature. In SCZ, then, at a neuroimmune response level, we found that multiple key hallmark pathways were implicated, including dopaminergic synapse p(<7.78e-9) [40,41], and signaling by both Receptor Tyrosine Kinase (p<1.86e-10) [42,43] and cGMP-PKG (p<2.94e-7) [44]. From an oligodendrocyte-based context, we observed that multiple forms of synapse function and regulation were enriched -specifically, the regulation of trans-synaptic signaling (p<1.95e-8) [45], modulation of chemical synaptic transmission (p<1.80e-8) [46], and neuron-to-neuron synapses (p<2.57e-11) [47].…”

Molecular signaling pathways underlying schizophrenia

“…Therefore, on the basis of the dopamine hypothesis, it was believed for decades that the main pathophysiology underlying the clinical phenotype was a defect in the dopaminergic system [1].…”

“…However, only a minority of patients reach full recovery or remission when treated with medications currently available, and, especially, negative and cognitive symptoms are commonly resistant to existing antipsychotic treatments [1]. There is increasing evidence that, in addition to dopaminergic defects, also abnormal glutamatergic, GABAergic, and serotoninergic signaling, as well as inflammation and oxidative stress contribute to the pathophysiology of schizophrenia [1,2].…”