Neurophysiological analysis of schizophrenia based on dysfunction of the glutamatergic system using a tripartite synapse model

Abstract

Schizophrenia is a severe chronic psychiatric disorder and its pathology is still not completely known. However, up to now several different theories have been proposed to describe the pathophysiology of schizophrenia. Hypofunction of NMDA receptors (NMDAR) and inactivated astrocytes are among important glutamatergic theories explaining the pathophysiology of schizophrenia. On the other hand, it has been suggested that pharmacological manipulation of presynaptic metabotropic glutamate receptors (mGluRs) may help to treat and improve some symptoms of schizophrenia. In this paper we propose a mathematical model at the synaptic level to investigate glutamatergic hypothesis of schizophrenia. In the proposed model, we described mathematically a single tripartite synapse that is consisted of one presynaptic and one postsynaptic neuron and a glial component that is the astrocyte. The proposed model describes different details of a tripartite synapse during glutamate release. To the best of our knowledge, at the moment this is the most extended mathematical model developed to describe the details of a tripartite synapse to this extend. Simulation results of the proposed model indicate that hypofunction of NMDAR might be caused by excessive amount of glutamate in the synaptic cleft. The increased amount of glutamate, in final analysis, can be caused by inactive astrocyte. The increased amount of glutamate in synaptic cleft may cause serious disturbances in NMDAR current and electrophysiological behavior of the postsynaptic neuron. Given these results, we suggest that manipulation of glutamate receptors on astrocyte may be a suitable strategy in the treatment of schizophrenia. Of course, other approaches that help to improve the function of glutamate transmission or use agonists of mGluRs or NMDARs might be also useful. Our simulation results also suggest that the mentioned theories about pathophysiology of schizophrenia are interrelated and the increased rate of clearance of glutamate from the synaptic cleft can partly compensate for disorders caused by the impaired astrocyte.