Connectivity analyses of bioenergetic changes in schizophrenia: Identification of novel treatments

Courtney R. Sullivan; Catharine A. Mielnik; Sinead M. O’Donovan; Adam J. Funk; Eduard Bentea; Erica A.K. DePasquale; Zhexing Wen; Vahram Haroutunian; Pavel Katsel; Amy J. Ramsey; Jarek Meller; Robert E. McCullumsmith

Finally, we assessed sensorimotor gating using pre-pulse inhibition and acoustic startle response (Figure 8 Our findings suggest that pioglitazone may selectively exert its effects on specific endophenotypes of schizophrenia, suggesting circuit-specific modulation of neuroplastic substrates. One possibility is that pioglitazone improves the function of brain regions and circuits that are hypometabolic, while having no effect/negative consequences on brain regions that are normal or hypermetabolic. Many behavioral endpoints that are markers of "positive symptoms" of schizophrenia could correspond to "hypermetabolic" circuitry, and thus not be amenable to rescue via pioglitazone. We found pioglitazone had no effect on behavioral deficits such as hyperactivity, increased stereotypy, and social impairments, which are normalized by typical and atypical antipsychotics in GluN1 knockdown animals (39, 41, (120) (121) (122) (123) . However, pioglitazone did have a restorative effect on cognition (puzzle box assay), while typical antipsychotics do not . CC-BY-NC-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/338392 doi: bioRxiv preprint (7, 124) . Studies examining the effects of antipsychotic treatment on cognition in GluN1 knockdown animals has not yet been done and are warranted.