Brain Acidity Linked with Multiple Neurological Disorders

In a global research effort, scientists have uncovered a relationship between metabolism problems in the brain and a range of neuropsychiatric and neurodegenerative disorders, from autism to Alzheimer's disease and more.

Despite their diverse symptoms, these conditions – as well as depression, epilepsy, schizophrenia, intellectual disability, and bipolar disorder – all involve a degree of cognitive impairment and often sharegenetic or metabolic features, hinting at a common biological basis.

The extensive collaboration by the International Brain pH Project Consortium, involving 131 scientists from 105 labs in seven countries, identified changes in brain acidity and lactate levels in animals as key signs of this metabolic dysfunction.

"We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism," the team writes in their published paper.

"However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain."

Their findings may lead to new ways of diagnosing and treating these complex disorders, that affect a large portion of the global population.

"This research could be a stepping stone towards identifying shared therapeutic targets in various neuropsychiatric disorders," says molecular and cellular physiologist Masayuki Matsushita from University of the Ryukyus in Japan.

Lactate changes can impact information transfer in neurons by disrupting the functional balance between excitatory and inhibitory brain networks. Increases in lactate levels in the brain can result in lower pH, which evidence suggests is another common feature in most of the disorders studied here.

By examining whole brain samples of multiple animal models, including mice, rats, and chicks, some modified genetically to mimic different neuropsychiatric and neurodegenerative diseases, the team found consistent shifts in brain pH and lactate levels.

"This is the first and largest systematic study evaluating brain pH and lactate levels across a range of animal models for neuropsychiatric and neurodegenerative disorders," says first author Hideo Hagihara, a medical scientist at Fujita Health University in Japan.

Remarkably, around 30 percent of the 2,294 animals studied, across 109 different models, displayed significant changes in pH and lactate levels. This implies these disruptions are common in many neuropsychiatric conditions.

Animal models representing depression induced by stress, diabetes, or colitis – all of which lead to higher risk of depression – displayed a consistent pattern of decreased brain pH and increased lactate levels.

This suggests various genetic or environmental factors that might induce these differences, such as inflammation, might influence brain metabolism and contribute to development of neuropsychiatric conditions.

Diverse responses were seen in autism models, with some exhibiting an increase in pH and a decrease in lactate levels while others showed the opposite pattern. This hints there could be various subgroups of metabolic dysfunctions among individuals with autism spectrum disorders.

And in behavioral tests, the team noted a strong link between high lactate levels and impaired working memory performance, which they say shows metabolic dysfunctions may directly impact cognitive abilities in various neuropsychiatric disorders.

Mitochondrial dysfunction is linked to several neuropsychiatric disorders which often exhibit working memory deficits as a common symptom. Mitochondrial dysfunction in neurons may result in less lactate consumption for energy production, with its accumulation potentially leading to impaired learning and memory functions.

But lactate production is necessary for memory formation too, so decreased levels could also contribute to dysfunction.

Overall, the authors say their results indicate that changes in brain pH and lactate levels, even if the changes contribute to a benefit, may serve as biological markers for neuropsychiatric disorders that come with cognitive impairment.

"Future studies will center on uncovering treatment strategies that are effective across diverse animal models with brain pH changes," Miyakawa says.

"This could significantly contribute to developing tailored treatments for patient subgroups characterized by specific alterations in brain energy metabolism."

The research has been published in eLife.