Abstract
N-methyl-D-aspartate (NMDA) receptor hypofunction has been implicated in the pathophysiology of schizophrenia. The illness is also characterized by gamma oscillatory disturbances, which can be evaluated with precise frequency specificity employing auditory cortical entrainment paradigms. This computational study investigates how synaptic NMDA hypofunction may give rise to network level oscillatory deficits as indexed by entrainment paradigms. We developed a computational model of a local cortical circuit with pyramidal cells and fast-spiking interneurons (FSI), incorporating NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA), and γ-aminobutyric acid (GABA) synaptic kinetics. We evaluated the effects of varying NMDA conductance on FSIs and pyramidal cells, as well as AMPA to NMDA ratio. We also examined the differential effects across a broad range of entrainment frequencies as a function of NMDA conductance. Varying NMDA conductance onto FSIs revealed an inverted-U relation with network gamma whereas NMDA conductance onto the pyramidal cells had a more monotonic relationship. Varying NMDA vs. AMPA conductance onto FSIs demonstrated the necessity of AMPA in the generation of gamma while NMDA receptors had a modulatory role. Finally, reducing NMDA conductance onto FSI and varying the stimulus input frequency reproduced the specific reductions in gamma range (~40 Hz) as observed in schizophrenia studies. Our computational study showed that reductions in NMDA conductance onto FSIs can reproduce similar disturbances in entrainment to periodic stimuli within the gamma range as reported in schizophrenia studies. These findings provide a mechanistic account of how specific cellular level disturbances can give rise to circuitry level pathophysiologic disturbance in schizophrenia.
Highlights
Cognitive dysfunction is a core feature of schizophrenia that is the best predictor of functional outcome but is poorly treated by current medications (Green, 2006)
To examine the effects of NMDA receptors in fast-spiking interneurons (FSI) on the network rhythms, we simulated a cortical model composed of quadratic integrate-and-fire neurons, examining how network gamma power varied with respect to NMDA conductance changes
In the current study, we investigated the role of NMDA receptors on cortical oscillations in a simulated neural network and can draw several conclusions from our observations
Summary
Cognitive dysfunction is a core feature of schizophrenia that is the best predictor of functional outcome but is poorly treated by current medications (Green, 2006). One of the prevailing pathophysiologic hypotheses for cognitive disturbance in schizophrenia is the hypofunction of glutamate NMDA receptors (Javitt, 1987). NMDA receptor antagonists [e.g., phencyclidine (PCP) and ketamine] induce symptoms closely resembling schizophrenia, including the cognitive deficits (Javitt, 1987), while exacerbating symptoms in patients (Krystal et al, 1994). NMDA blockade through PCP and ketamine has been used in rodent (Moghaddam and Jackson, 2003) and nonhuman primate (Gil-da-Costa et al, 2013) models of schizophrenia. Together, these findings are consistent with a role for NMDA receptor hypofunction in the pathophysiology of schizophrenia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
