In silico hippocampal modeling for multi-target pharmacotherapy in schizophrenia

Treatment of schizophrenia has had limited success in treating core cognitive symptoms. The evidence of multi-gene involvement suggests that multi-target therapy may be needed. Meanwhile, the complexity of schizophrenia pathophysiology and psychopathology, coupled with the species-specificity of much of the symptomatology, places limits on analysis via animal models, in vitro assays, and patient assessment. Multiscale computer modeling complements these traditional modes of study. Using a hippocampal CA3 computer model with 1200 neurons, we examined the effects of alterations in NMDAR, HCN (I_h current), and GABA_AR on information flow (measured with normalized transfer entropy), and in gamma activity in local field potential (LFP). We found that altering NMDARs, GABA_AR, I_h, individually or in combination, modified information flow in an inverted-U shape manner, with information flow reduced at low and high levels of these parameters. Theta-gamma phase-amplitude coupling also had an inverted-U shape relationship with NMDAR augmentation. The strong information flow was associated with an intermediate level of synchrony, seen as an intermediate level of gamma activity in the LFP, and an intermediate level of pyramidal cell excitability. Our results are consistent with the idea that overly low or high gamma power is associated with pathological information flow and information processing. These data suggest the need for careful titration of schizophrenia pharmacotherapy to avoid extremes that alter information flow in different ways. These results also identify gamma power as a potential biomarker for monitoring pathology and multi-target pharmacotherapy.