Abstract
In vivo 1H magnetic resonance spectroscopy studies have found elevated brain glutamate or glutamate + glutamine levels in bipolar disorder with surprisingly high reproducibility. We propose that the elevated glutamate levels in bipolar disorder can be explained by increased pyruvate carboxylase-mediated anaplerosis in brain. Multiple independent lines of evidence supporting increased pyruvate carboxylase-mediated anaplerosis as a common mechanism underlying glutamatergic hyperactivity in bipolar disorder and the positive association between bipolar disorder and obesity are also described.
Highlights
The etiologic and disease mechanisms of bipolar disorder remain poorly understood
Because of the unique role of pyruvate carboxylase in brain glutamate formation the highly consistent findings of elevated glutamate or glutamate + glutamine levels in bipolar disorder observed by in vivo 1H magnetic resonance spectroscopy (MRS), serum and post-mortem studies can be readily explained by increased pyruvate carboxylase-mediated anaplerosis in brain of patients with bipolar disorders
The elevated glutamate + glutamine levels are consistent with mitochondrial dysfunction and a chronic mismatch between glucose utilization and oxidative metabolism in bipolar disorder accompanied by incomplete carbohydrate oxidation and increased pyruvate carboxylase-mediated anaplerosis
Summary
The etiologic and disease mechanisms of bipolar disorder remain poorly understood. A growing body of evidence indicates a central role of mitochondrial dysfunction in the pathophysiology of bipolar disorder. Post-mortem brain studies have revealed abnormal size, structure and distribution of mitochondria as well as a pronounced and extensive decrease in nuclear gene expression governing oxidative phosphorylation in bipolar disorder [1,2,3] These post-mortem results are consistent with in vivo findings of elevated cerebrospinal fluid pyruvate and lactate levels [4, 5], decreased adenosine triphosphate production and a significant shift from oxidative phosphorylation to glycolysis in brain in bipolar disorder accompanied by elevated brain lactate levels and lowered intracellular pH as reported by in vivo 31P and 1H magnetic resonance spectroscopy (MRS) studies [6,7,8,9,10]. The pyruvate carboxylase-mediated anaplerotic pathway may represent future therapeutic targets for bipolar disorder
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