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.

Opposite effects of positive and negative symptoms on resting-state brain networks in schizophrenia

“…A recent meta-analysis on lactate or pH in schizophrenia revealed a significant increase in lactate in schizophrenia and a nonsignificant decrease in pH 85 . Our GO enrichment results provide further evidence that abnormal metabolic processes in schizophrenia brains result in the accumulation of ammonia, inducing hyperammonemia, acidosis and increased serum lactate 50 . All these abnormalities are closely related to schizophrenia 50,86 , especially acidosis altering dopamine and glutamate neurotransmission, causing symptoms of schizophrenia 50 .…”

“…Overall, the effect of SANS is related to synaptic signaling processes and abnormal autistic, aggressive and violent behavior; the effect of SAPS is related to metabolic precursors, hyperammonemia and acidosis; and the SANSSAPS interaction effect is related to cellular localization and transport and abnormal motor function. All these phenotypes have been found in schizophrenia 46,47,48,49,50 .…”

Hydrogen Ion Dynamics as the Fundamental Link Between Neurodegenerative Diseases and Cancer. Its Application to the Therapeutics of Neurodegenerative Diseases with Special Emphasis in Multiple Sclerosis

“…Lately, the study of the dynamics of the H + in medical research, mainly in cancer, has been extended sideways to include from the field of theoretical physics [73] to, most recently, even the pathogenesis of schizophrenia [74]. This contribution also aims to revive and actualize these classical seminal concepts on systemic homeostasis and physiopathology in order to apply them to the fields of neurology and oncology, but now at a cellular and microenvironmental level.…”

Stress-induced reduction of Na + /H + exchanger isoform 1 promotes maladaptation of neuroplasticity and exacerbates depressive behaviors

“…The brain is highly sensitive to shifts in pH due to proteins involved in regulating neuronal excitability, and effective synaptic transmission is critically dependent on appropriate pH levels (10). There is growing evidence that intracellular pH (pHi) changes in the brain are associated with cognitive, emotional, and psychotic behaviors, and a significant decrease in neuronal pHi may be associated with the severity of depression (11)(12)(13). In this way, changes in homeostasis characteristics caused by intracellular acidification may be a key link between external stress and internal dysfunction.…”