Wide-ranging Animal Studies Link pH Changes to Cognitive and Psychiatric Disorders
A global collaborative research group has identified brain energy metabolism dysfunction leading to altered pH and lactate levels as common hallmarks in numerous animal models of neuropsychiatric and neurodegenerative disorders. These include models of intellectual disability, autism spectrum disorders, schizophrenia, bipolar disorder, depressive disorders, and Alzheimer’s disease. The findings were published in eLife.
The research group, comprising 131 researchers from 105 laboratories across seven countries, sheds light on altered energy metabolism as a key factor in various neuropsychiatric and neurodegenerative disorders. While considered controversial, an elevated lactate level and the resulting decrease in pH is now also proposed as a potential primary component of these diseases. Unlike previous assumptions associating these changes with external factors like medicationa, the research group’s previous findings suggest that they may be intrinsic to the disorders. This conclusion was drawn from five animal models of schizophrenia/developmental disorders, bipolar disorder, and autism, which are exempt from such confounding factorsb. However, research on brain pH and lactate levels in animal models of other neuropsychiatric and neurological disorders has been limited. Until now, it was unclear whether such changes in the brain were a common phenomenon. Additionally, the relationship between alterations in brain pH and lactate levels and specific behavioural abnormalities had not been clearly established.
This study, encompassing 109 strains/conditions of mice, rats, and chicks, including animal models related to neuropsychiatric conditions, reveals that changes in brain pH and lactate levels are a common feature in a diverse range of animal models of conditions, including schizophrenia/developmental disorders, bipolar disorder, autism, as well as models of depression, epilepsy, and Alzheimer’s disease. This study’s significant insights include:
I. Common Phenomenon Across Disorders: About 30% of the 109 types of animal models exhibited significant changes in brain pH and lactate levels, emphasising the widespread occurrence of energy metabolism changes in the brain across various neuropsychiatric conditions.
II. Environmental Factors as a Cause: Models simulating depression through psychological stress, and those induced to develop diabetes or colitis, which have a high comorbidity risk for depression, showed decreased brain pH and increased lactate levels. Various acquired environmental factors could contribute to these changes.
III. Cognitive Impairment Link: A comprehensive analysis integrating behavioural test data revealed a predominant association between increased brain lactate levels and impaired working memory, illuminating an aspect of cognitive dysfunction.
IV. Confirmation in Independent Cohort: These associations, particularly between higher brain lactate levels and poor working memory performance, were validated in an independent cohort of animal models, reinforcing the initial findings.
V. Autism Spectrum Complexity: Variable responses were noted in autism models, with some showing increased pH and decreased lactate levels, suggesting subpopulations within the autism spectrum with diverse metabolic patterns.
“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. Our findings may lay the groundwork for new approaches to develop the transdiagnostic characterisation of different disorders involving cognitive impairment,” states Dr Hideo Hagihara, the study’s lead author.
Professor Tsuyoshi Miyakawa, the corresponding author, explains, “This research could be a stepping stone towards identifying shared therapeutic targets in various neuropsychiatric disorders. Future studies will centre on uncovering treatment strategies that are effective across diverse animal models with brain pH changes. This could significantly contribute to developing tailored treatments for patient subgroups characterized by specific alterations in brain energy metabolism.”
The exact mechanism behind the reduction in pH and the increase in lactate levels remains elusive. But the authors suggest that, since lactate production increases in response to neural hyperactivity to meet the energy demand, this might be the underlying reason.
Source: Fujita Health University
