Studying the effect of dysregulation of NMDA receptors function in schizophrenia

Abstract

There are several neuropsychological theories about the pathology of schizophrenia, one of which is the glutamate theory. This theory suggests that hypofunction of NMDA receptors, which may be caused by dysfunction or dysregulation of NMDA receptors, leads to symptoms of schizophrenia. On the other hand, inactivated astrocyte and decreased levels of D-Serine concentration have also been considered to be involved in the etiology of schizophrenia. In the present study, the model of a single tripartite synapse that is consisted of one presynaptic and one postsynaptic neuron and a glial component (the astrocyte) is improved and extended. In our proposed model, the model of NMDAR current is explained with more details and the model of the D-serine modulator dynamics is added to the model. Later, the model of the tripartite synapse is impaired based on the pathology of schizophrenia. Simulation results of the pathologic tripartite synapse model indicate that roles of the three factors which might cause the pathology of schizophrenia are interrelated. The impaired astrocyte can leads to dysfunction of glutamatergic transmission system and hypofunction of NMDA receptors. According to these results, the role of astrocytes in the pathophysiology of schizophrenia should be considered seriously. The astrocytes also can serve as a target for pharmacotherapy of schizophrenia to improve its symptoms. On the other hand, simulation results suggest that increased glutamate and decreased D-serine concentration can lead to the reduction in the amplitude and the number of oscillations of the NMDAR currents. Furthermore, these deficits lead to changes in the presynaptic firing mode, such that the bursting activity will be off. Based on the proposed model, increasing the rate of glutamate clearance and the D-serine concentration in the synaptic cleft will mostly compensate the dysregulation of NMDAR function and impaired postsynaptic potential, and the behavior of the synapse will return to its normal condition. However, if the conductance of the NMDA receptor channels is decreased or the blockade of magnesium ions on NMDAR channels is increased, these methods will not be effective anymore and cannot compensate the deficits related to schizophrenia. Therefore, our results confirm that dysregulation of NMDA receptors function is responsible for the pathophysiology of schizophrenia more than their dysfunction.