Minocycline Reduces Synaptic Pruning in Schizophrenia Cell Models

February 11, 2019

By Will Boggs MD

NEW YORK—Minocycline reduces excessive synaptic pruning in schizophrenia patient-derived cell models, suggesting that it might delay or prevent the onset of schizophrenia in some individuals, according to new research.

"After years of looking, for the first time, we see differences in synapses between schizophrenia patients and healthy controls," Dr. Roy H. Perlis from Massachusetts General Hospital and Harvard Medical School, in Boston, told Reuters Health by email. "And we can potentially use this finding to look for new treatments."

Postmortem studies of people with schizophrenia have shown reduced numbers of dendritic spines, and researchers have suggested that excessive synaptic pruning by microglia in late adolescence and early adulthood could be responsible. Differences between human and rodent microglia and the inability to model microglial functions in humans using patient-derived primary cells have limited efforts to test this hypothesis.

Dr. Perlis and colleagues used their recently developed in vitro model of microglia-mediated synapse engulfment by patient-derived cells to compare features of synaptic pruning in cells derived from schizophrenia patients and from matched controls without the disorder.

Schizophrenia-patient-derived cells showed increased engulfment of synaptic structures influenced by both neuronal and microglial factors, compared with healthy control-derived cells.

The uptake of synaptic structures in schizophrenia-patient-derived cells depended largely on C3-C3 receptor interactions that appear to be related to increased C4A expression in neurons resulting from variability at the C4 genetic locus.

Minocycline treatment of cells derived from schizophrenia patients and healthy controls showed dose-dependent decreases in microglial engulfment of synaptic structures, the researchers report in Nature Neuroscience, online February 4.

In a preliminary proof-of-concept analysis of electronic health records, minocycline or doxycycline exposure for at least 90 days during adolescence was associated with a 42% decreased risk of incident psychosis, after adjustment for age, sex, self-reported ethnicity, and year of database entry.

"Taken in aggregate, our work supports increased synapse elimination in schizophrenia, offering a mechanism linking known genetic risk variants to observed structural brain changes in early disease," the researchers conclude. "Specific pharmacological interventions targeting microglial elimination of synapses merit further study for their capacity to delay or prevent the onset of schizophrenia in high-risk individuals."

"Now that we understand at least one aspect of what may be wrong in schizophrenia, we can use it to look for treatments," Dr. Perlis said. "The past 5 decades have been about treating schizophrenia symptoms. Our hope is that, with this paper, we can begin to pivot towards prevention. We need more studies that try to prevent disease, not just control symptoms once they've full emerged."

Dr. Etienne Audinat of the University of Montpellier's Institute of Functional Genomics, in France, who recently reviewed the role of microglia in central-nervous-system development, told Reuters Health by email, "This approach is extremely powerful and opens the door to the study of many human neurological and psychiatric disorders for which evidence indicates a role of microglia (many if not all brain disorders). The important point here is the use of human cells, a powerful complementary option to the use of animal models that suffer from many limitations."

"Microglial cells are key players of brain disorders, even of pathologies for which, until recently, we did not expect the involvement of immune cells," he said. "It should be stressed, however, that besides genetic factors, brain environment during development (e.g., maternal immune activation) has been also proposed to influence the risk to develop psychiatric diseases and, if true, microglia are perfectly positioned to be crucial here, too."

Dr. Audinat, who was not involved in the new work, added, "Minocycline has paradoxical effects during development and can lead to massive neuronal death, in part by preventing microglia from releasing growth factors. It also has peripheral effects due to its action on macrophages that regulates the growth of different other organs. This is, therefore, not a therapeutic option during early stages of development. In addition, minocycline has many other effects than just inhibiting some microglia functions."

Five of Dr. Perlis' coauthors were employed by Novartis.

SOURCE: https://bit.ly/2DmXQUP

Nat Neurosci 2019.

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