Sustained NMDA receptor hypofunction induces compromised neural systems integration and schizophrenia-like alterations in functional brain networks.
Compromised functional integration between cerebral subsystems and dysfunctional brain network organization may underlie the neurocognitive deficits seen in psychiatric disorders. Applying topological measures from network science to brain imaging data allows the quantification of complex brain network connectivity. While this approach has recently been used to further elucidate the nature of brain dysfunction in schizophrenia, the value of applying this approach in preclinical models of psychiatric disease has not been recognized. For the first time, we apply both established and recently derived algorithms from network science (graph theory) to functional brain imaging data from rats treated subchronically with the N-methyl-D-aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). We show that subchronic PCP treatment induces alterations in the global properties of functional brain networks akin to those reported in schizophrenia. Furthermore, we show that subchronic PCP treatment induces compromised functional integration between distributed neural systems, including between the prefrontal cortex and hippocampus, that have established roles in cognition through, in part, the promotion of thalamic dysconnectivity. We also show that subchronic PCP treatment promotes the functional disintegration of discrete cerebral subsystems and also alters the connectivity of neurotransmitter systems strongly implicated in schizophrenia. Therefore, we propose that sustained NMDA receptor hypofunction contributes to the pathophysiology of dysfunctional brain network organization in schizophrenia.
Psychiatric Research Institute of Neuroscience in Glasgow (PsyRING), Glasgow, UK.
Neil
N
Dawson
Xiaolin
X
Xiao
Martin
M
McDonald
Desmond J
DJ
Higham
Brian J
BJ
Morris
Judith A
JA
Pratt
D000465:Algorithms; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D001931:Brain Mapping; D002250:Carbon Radioisotopes; D003847:Deoxyglucose / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D010622:Phencyclidine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D011877:Radionuclide Imaging; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012559:Schizophrenia / Q000503:physiopathology; D012815:Signal Processing, Computer-Assisted; D018511:Systems Integration; D013788:Thalamus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology
D002250:Carbon Radioisotopes; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D003847:Deoxyglucose; D010622:Phencyclidine