The Role of Astrocytes in the Pathophysiology of Schizophrenia.

Glutamate;Postmortem;Glia;Neurosciences;Health Sciences;Neuroscience

Steffek, Amy E.Ann Arbor ;

University of Michigan

关键词: Glutamate;    Postmortem;    Glia;    Neurosciences;    Health Sciences;    Neuroscience;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/55679/asteffek_1.pdf?sequence=2&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

A glutamate hypothesis of schizophrenia emerged based on pharmacological evidence that N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), can induce symptoms similar to those seen in schizophrenia.Subsequently, abnormal expression of various neuronal molecules associated with the glutamate synapse has been reported in schizophrenia.Astrocytes, a prominent glial cell in the brain, play a significant role in maintaining the structure and integrity of neural tissue and in facilitating excitatory neurotransmission, therefore, any breakdown in the structure or function of astrocytes could disrupt neuronal signaling and disturb brain function.I studied structural and functional molecules in astrocytes to determine 1) whether astrocytes are themselves globally compromised in schizophrenia, and 2) whether abnormal expression of glutamatergic molecules in astrocytes could be a contributing factor to brain dysfunction in this illness.I examined the expression of molecular markers of astrocytes as a measure of the integrity of these cells in schizophrenia.S100B, a calcium binding protein previously shown to be increased in the plasma and CSF of patients with schizophrenia, was not altered.I found that the intermediate-filament glial fibrillary acidic protein (GFAP), a component of the astrocyte cytoskeleton, was significantly altered in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in schizophrenia.I also measured the expression of two astrocytic enzymes involved in glutamate function: glutamine synthetase, involved in recycling synaptic glutamate, and serine racemase, which synthesizes the NMDA receptor co-agonist D-serine.Glutamine synthetase was significantly decreased in the superior temporal gyrus and ACC, and protein expression of serine racemase was increased in the hippocampus in schizophrenia.This was the first study to demonstrate altered expression of glutamine synthetase in these brain regions, and the first report of serine racemase expression abnormalities in schizophrenia.These findings suggest that astrocytes contribute to the pathophysiology of schizophrenia and that astrocytic molecules involved in cytoskeletal integrity and glutamatergic function are compromised in this illness.Schizophrenia is a complex illness that requires a reappraisal of the existing neuronal model to include an astrocytic hypothesis of dysfunction, which could lead to a better understanding of schizophrenia, and provide novel treatment strategies in this illness.