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

We sought to replicate our metabolic LCM findings, as well as explore the mRNA expression of seed genes through in silico "lookup" analyses (18) . In our LCM studies, we found decreases in HK1, PFKM, PFKL, and GPI in pyramidal neurons in the DLPFC in schizophrenia ( Figure 2 , Table 2 )(18). We probed a second cell-level dataset (frontal cortical neurons differentiated from IPSCs of schizophrenia subjects with the DISC mutation (75)) and found that 5/6 of our seed genes were abnormally expressed (LDHA, HK1, PFKM, PFKL, and GPI) ( Table 2 )(75). LDHA, which was previously found to be downregulated in dentate granule neurons in schizophrenia, was also significantly downregulated in the SMRI genomics database (15) . We also found that PFKFB2, which is genetically linked to schizophrenia, is downregulated in schizophrenia in the MSSM DLPFC microarray data (14) . The SMRI and the MSSM databases contain region-level findings in multiple brain regions, while IPSCs and LCM techniques provide cell-subtype specific resolution. Further, prior work in our laboratory found a decrease in PFK and HK enzyme activity levels in the DLPFC in schizophrenia (18) . These findings suggest our seed genes are dysregulated at the cell, region, transcript, and functional level in schizophrenia, as well as by genetic association.