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.
Highlights
Schizophrenia is a devastating illness that affects 1% of the general population and displays a wide range of psychotic symptoms, as well as cognitive deficits and profound negative symptoms that are often treatment resistant[1,2,3,4,5]
We supplemented these studies by measuring lactate in two animal models of schizophrenia and inducible pluripotent stem cells from patients, allowing us to control for the effects of antipsychotic medication, postmortem interval, and other factors that limit interpretation of postmortem brain studies
In cell lysates from frontal cortical neurons differentiated from inducible pluripotent stem cells (iPSCs) from a schizophrenia patient, we found a significant increase (37%) in lactate compared to frontal cortical neurons differentiated from an unaffected family member (p < 0.0001) (Fig. 1)
Summary
Schizophrenia is a devastating illness that affects 1% of the general population and displays a wide range of psychotic symptoms, as well as cognitive deficits and profound negative symptoms that are often treatment resistant[1,2,3,4,5]. A study employing high field (7T) MRS demonstrated elevated in vivo brain lactate levels in patients with schizophrenia, possibly indicating metabolic dysfunction with a shift towards anaerobic glycolysis[17] These elevations in lactate were associated with lower general cognitive function and functional capacity in the total sample, including visual learning, processing speed, and reasoning/problem solving cognitive domains (n = 31/group)[17]. Postmortem studies have reported elevated lactate levels in the striatum and cerebellum in schizophrenia subjects versus controls[19,20] Despite these findings, there is some controversy regarding whether or not changes in lactate are part of a pathological mechanism related to the illness, or altogether secondary to the effects of medication or other postmortem factors that may impact lactate levels. We supplemented these studies by measuring lactate in two animal models of schizophrenia and inducible pluripotent stem cells (iPSCs) from patients, allowing us to control for the effects of antipsychotic medication, postmortem interval, and other factors that limit interpretation of postmortem brain studies
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