Decreased Brain pH and Pathophysiology in Schizophrenia

Abstract

Postmortem studies reveal that the brain pH in schizophrenia patients is lower than normal. The exact cause of this low pH is unclear, but increased lactate levels due to abnormal energy metabolism appear to be involved. Schizophrenia patients display distinct changes in mitochondria number, morphology, and function, and such changes promote anaerobic glycolysis, elevating lactate levels. pH can affect neuronal activity as H⁺ binds to numerous proteins in the nervous system and alters the structure and function of the bound proteins. There is growing evidence of pH change associated with cognition, emotion, and psychotic behaviors. Brain has delicate pH regulatory mechanisms to maintain normal pH in neurons/glia and extracellular fluid, and a change in these mechanisms can affect, or be affected by, neuronal activities associated with schizophrenia. In this review, we discuss the current understanding of the cause and effect of decreased brain pH in schizophrenia based on postmortem human brains, animal models, and cellular studies. The topic includes the factors causing decreased brain pH in schizophrenia, mitochondria dysfunction leading to altered energy metabolism, and pH effects on the pathophysiology of schizophrenia. We also review the acid/base transporters regulating pH in the nervous system and discuss the potential contribution of the major transporters, sodium hydrogen exchangers (NHEs), and sodium-coupled bicarbonate transporters (NCBTs), to schizophrenia.

Keywords: brain pH; dopamine; glutamate; lactate; mitochondria dysfunction; pH-regulating proteins; schizophrenia.

Figure 1

Model for the effect of decreased brain pH on schizophrenia. (A) Overview of the model. Mitochondrial dysfunction in schizophrenia causes anaerobic metabolism that elevates lactate levels, resulting in lactic acidosis. Acidosis alters dopamine and glutamate neurotransmission, causing symptoms of schizophrenia. Enhanced release of dopamine and glutamate may conversely increase an energy demand in neurons and astrocytes, promoting elevated production of lactic acid, which aggravates acidosis. (B) Synaptic pH regulation in schizophrenia. Enhanced dopamine release and hyperactivated D2 receptors stimulate NHE1, which compensates intracellular acidification while inducing extracellular acidification. At glutamatergic synapses, NBCn1 in postsynaptic neurons decreases the NMDA receptor activity by preventing the interaction with the receptors. NHE9 in astrocytes increases the plasma membrane expression of glutamate transporters to increase glutamate uptake.