Measurement of lactate levels in postmortem brain, iPSCs, and animal models of schizophrenia

Abstract

Converging evidence suggests bioenergetic defects contribute to the pathophysiology of schizophrenia and may underlie cognitive dysfunction. The transport and metabolism of lactate energetically couples astrocytes and neurons and supports brain bioenergetics. We examined the concentration of lactate in postmortem brain (dorsolateral prefrontal cortex) in subjects with schizophrenia, in two animal models of schizophrenia, the GluN1 knockdown mouse model and mutant disrupted in schizophrenia 1 (DISC1) mouse model, as well as inducible pluripotent stem cells (iPSCs) from a schizophrenia subject with the DISC1 mutation. We found increased lactate in the dorsolateral prefrontal cortex (p = 0.043, n = 16/group) in schizophrenia, as well as in frontal cortical neurons differentiated from a subject with schizophrenia with the DISC1 mutation (p = 0.032). We also found a decrease in lactate in mice with induced expression of mutant human DISC1 specifically in astrocytes (p = 0.049). These results build upon the body of evidence supporting bioenergetic dysfunction in schizophrenia, and suggests changes in lactate are a key feature of this often devastating severe mental illness.

Figure 1

Lactate levels expressed as %CTL (or wildtype). Lactate concentration (nmoles/µg protein) measured in the dorsolateral prefrontal cortex (DLPFC) of control subjects (CTL) and subjects with schizophrenia (SCZ) expressed as % CTL. Lactate concentration was also measured in frontal cortex tissue homogenate from GluN1 knockdown (KD) mice (versus wildtype), the mutant disrupted in schizophrenia 1 (DISC1) mouse model with inducible expression of mutant human DISC1 in GFAP or CAMK positive cells (versus wildtype), cell lysates of inducible pluripotent stem cells from a schizophrenia patient (n = 6 technical replicates) with a mutation in the DISC1 gene differentiated into frontal cortical neurons (CN) (versus unaffected family member), and prefrontal cortex homogenate from rats treated with the antipsychotic (AP) haloperidol-deaconate (28.5 mg/kg q 3 weeks) (versus vehicle) for 9 months. Data are expressed as mean ± SEM. *P < 0.05.

Figure 2

Correlation analyses. Bivariate plots (linear regression) of lactate concentration (nmoles/µg protein) versus pH (a), postmortem interval (PMI) (b), or age (c) in dorsolateral prefrontal cortex (DLPFC) in all control (CTL) subjects and subjects with schizophrenia (SCZ). Outliers removed with ROUT method (Q = 5%).

Figure 3

Lactate levels in rats simulating increasing PMIs. Lactate concentration (nmoles/µg protein) in the frontal cortex of rats simulating varying postmortem intervals (PMIs) expressed as percent of 0 hour PMI. Data are expressed as mean ± SEM (n = 3 per group). *P < 0.05.