Abnormal Glutamatergic Neurotransmission and Neuronal-Glial Interactions in Acute Mania

Abstract

Background At excitatory synapses, glutamate released from neurons is taken up by glial cells and converted to glutamine, which is cycled back to neurons. Alterations in this system are believed to play a role in the pathophysiology of bipolar disorder, but they have not been characterized in vivo. We examined the glutamine/glutamate ratio, and levels of other metabolites in acute mania and schizophrenia in this exploratory study. Methods Data were obtained from 2×2×2cm voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) using 2-dimensional J-resolved proton magnetic resonance spectroscopy at 4 Tesla, and analyzed using LCModel. Fifteen bipolar disorder patients with acute mania and seventeen schizophrenia patients with acute psychosis were recruited from an inpatient unit; twenty one matched healthy controls were also studied. Glutamine/glutamate ratio and N-acetylaspartate, creatine, choline, and myo-inositol levels were evaluated in a repeated-measures design. Medication effects and relationship to demographic and clinical variables were analyzed. Results Glutamine/glutamate ratio was significantly higher in ACC and POC in bipolar disorder, but not schizophrenia, compared with healthy controls. N-acetylaspartate was significantly lower in the ACC in schizophrenia. Patients on and off lithium, anticonvulsants, or benzodiazepines had similar glutamine/glutamate ratios. Conclusions The elevated glutamine/glutamate ratio is consistent with glutamatergic overactivity and/or defective neuronal-glial coupling in acute mania, although medication effects cannot be ruled out. Abnormalities in glutamatergic neurotransmission and glial cell function in bipolar disorder may represent targets for novel therapeutic interventions.