Hypofunction of NMDA receptors due to the hyperactivation of dopamine receptors in the hippocampal synapses of schizophrenia based mathematical model

Abstract

Glutamate and dopamine hypothesizes are known in the pathophysiology of schizophrenia. Some recent experiments suggest that there is an interaction between them. We proposed a mathematical model for some of the abnormalities of schizophrenia in the synaptic level. First, we developed a healthy single tripartite synapse and after that the model according to the schizophrenia was impaired. The tripartite synapse is consisted of one presynaptic and one postsynaptic neuron and a glial component that is the astrocyte. In our developed model, the dynamics of dopamine and NMDAR current are added to a basic tripartite synapse. The results of pathologic model indicate that there is a strong connection between these two hypothesizes so that the NMDA receptors are highly affected from dopamine neurotransmission and hyperactive dopamine receptors. The increased activity of dopamine receptors lead to change in the intracellular processes of postsynaptic neuron such as IP3, Ca2+ and calmodulin. Increasing the calmodulin concentration reduces the NMDAR opening time and in general, it inhibits this receptor so that it leads to the conversion of postsynaptic voltage mode from bursting to single spiking. Our analysis of results indicates that the decreased fluctuations of NMDAR current are caused by dysfunction of dopamine neurotransmission. Our results in the synaptic level using a mathematical model express that hyperfunction of dopaminergic system may lead to the hypofunction of glutamatergic system. It is likely that such a disorder also occurs in schizophrenia synapses.