Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders

Abstract

Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. All mice were drug naive with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder.

Figure 1

Lower pH in the postmortem brains of patients with schizophrenia and bipolar disorder. Box plot of brain pH in control participants (white box), patients with schizophrenia (red box), and patients with bipolar disorder (blue box). The boxes represent the interquartile range between first and third quartiles, whereas the whiskers represent the maximum and minimum values, and the circles represent population outliers. ^*1P=0.020, ^*2P<0.0001, ^*3P=0.0001, ^*4P=0.027; ANOVA/Tukey’s post hoc test within each data set.

Figure 2

Lower pH and increased lactate levels in the brains of mouse models of psychiatric disorders. Bar graphs of pH (a), lactate levels (b), pyruvate levels (d), glucose levels (e), and ADP/ATP ratio (f) in the brains of Shn2 KO, Cn KO, Nrgn KO, Camk2a HKO, and Chd8 HKO mice and their corresponding controls (mean±SEM). Each plot represents individual mouse values. (c) Scatter plot showing correlations between pH and lactate levels in the mouse brain. Asterisks indicate statistically significant differences between controls and mutants after Bonferroni–Holm correction (*P<0.05, **P<0.01). ADP, adenosine diphosphate; ATP, adenosine triphosphate.