Analysis of impaired LTP in schizophrenia using an extended mathematical model of a tripartite synapse

One of the biological models presented in recent years to express the neuropathology of schizophrenia is based on an inactivated pathologic astrocyte in the tripartite synapse. In this study we developed a mathematical model of a tripartite synapse capable of expressing the pathologic behavior of the synapse under the aforementioned condition. Our results indicate that under pathologic conditions, there are increased nitric oxide (NO) feedback and decreased D-serine in the tripartite synapse that eventually lead to NMDAR hypofunction and subsequently abolishing of long term potentiation (LTP). Increased NO and lack of astrocytic glutamate in the synaptic cleft, which are happened after some intracellular processes, lead to increased release of glutamate from presynaptic neuron. Increased glutamate and at the same time lack of sufficient D-serine lead to fluctuations in NMDAR current with reduced amplitude and also reduced number of spikes and lower frequency in the postsynaptic potential. In other words, impaired synaptic neurotransmission, together with excessive NO-dependent phosphorylation of NMDA receptors, cause dysregulation of the NMDARs. Our results indicate that there is a mutual interaction between irregularities that lead to hypofunction of NMDARs. NMDAR activity is significantly degraded and there is not any stable and persistent LTP in the pathologic tripartite synapse. Based on our results, impairment of LTP is because of increase in the phosphorylation of CaMKII and unusual and severe oscillations with high amplitude and high frequency in the phosphorylated CaMKII concentration. Perhaps the reported deficiencies in the learning and memory and even other cognitive symptoms of schizophrenia are caused by the impaired LTP and the other mentioned impairments in the tripartite synapse especially D-serine shortage, the inactivated astrocyte and abnormalities occurred in the glutamatergic neurotransmission that are likely responsible for hypofunction of NMDA receptors. We suggest that manipulation of D-serine concentration or its binding site on the NMDA receptor and also increasing the activities of astrocytic receptors particularly mGluRs may be effective targets for therapeutic approaches.