Abstract
A large number of cellular level abnormalities have been identified in the hippocampus of schizophrenic subjects. Nonetheless, it remains uncertain how these pathologies interact at a system level to create clinical symptoms, and this has hindered the development of more effective antipsychotic medications. Using a 72-processor supercomputer, we created a tissue level hippocampal simulation, featuring multicompartmental neuron models with multiple ion channel subtypes and synaptic channels with realistic temporal dynamics. As an index of the schizophrenic phenotype, we used the specific inability of the model to attune to 40 Hz (gamma band) stimulation, a well-characterized abnormality in schizophrenia. We examined several possible combinations of putatively schizophrenogenic cellular lesions by systematically varying model parameters representing NMDA channel function, dendritic spine density, and GABA system integrity, conducting 910 trials in total. Two discrete “clusters” of neuropathological changes were identified. The most robust was characterized by co-occurring modest reductions in NMDA system function (-30%) and dendritic spine density (-30%). Another set of lesions had greater NMDA hypofunction along with low level GABA system dysregulation. To the schizophrenic model, we applied the effects of 1,500 virtual medications, which were implemented by varying five model parameters, independently, in a graded manner; the effects of known drugs were also applied. The simulation accurately distinguished agents that are known to lack clinical efficacy, and identified novel mechanisms (e.g., decrease in AMPA conductance decay time constant, increase in projection strength of calretinin-positive interneurons) and combinations of mechanisms that could re-equilibrate model behavior. These findings shed light on the mechanistic links between schizophrenic neuropathology and the gamma band oscillatory abnormalities observed in the illness. As such, they generate specific falsifiable hypotheses, which can guide postmortem and other laboratory research. Significantly, this work also suggests specific non-obvious targets for potential pharmacologic agents.
Highlights
Schizophrenia is a debilitating, lifelong illness affecting approximately 1% of the population worldwide [1]
Despite several years of research, and the introduction of a number of new agents, all currently used antipsychotics are far from ideal. They are capable of ameliorating some symptoms in many, though not all, schizophrenic patients, and none represents a cure to the disease
The model reproduced, in a quantitatively similar way, frequency behaviors shown in control subjects (Fig 1A [left panels] and 1B [left panels] experimental; Fig 1C [left panels] model output)
Summary
Schizophrenia is a debilitating, lifelong illness affecting approximately 1% of the population worldwide [1]. Despite several years of research, and the introduction of a number of new agents, all currently used antipsychotics are far from ideal They are capable of ameliorating some symptoms in many, though not all, schizophrenic patients, and none represents a cure to the disease. Deficiencies in GABAergic innervation have been seen, as a result of decreased number of particular subtypes of GABA neurons or GABAergic tone, and a (presumably compensatory) increase in postsynaptic GABA receptor expression [5]; (2) Glutamatergic system deficiency This is manifested, for example, as decreased expression of N-methyl-D-aspartic acid (NMDA) receptors, and/ or hypofunction of NMDA synaptic activity [6,7]; and (3) Decreases in brain connectivity. Diminished dendritic spine density has been seen, for example, in postmortem and animal models of the illness [8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
