Erythropoietin restrains the inhibitory potential of interneurons in the mouse hippocampus

Author: mycolabadmin
4/15/2024
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Summary

Researchers studied how a protein called erythropoietin (EPO) affects brain cells called interneurons in the hippocampus, a region important for memory and learning. They found that EPO treatment reduces the inhibitory activity of certain interneurons, which makes the brain’s excitatory neurons more active. This change in brain balance could potentially help treat psychiatric disorders like schizophrenia and autism that involve imbalanced brain activity.

Background

Severe psychiatric illnesses including schizophrenia, affective diseases, and autism spectrum disorders are associated with cognitive impairment and perturbed excitatory-inhibitory balance in the brain. Erythropoietin (EPO) has been shown to exert neuroprotective and neuroregenerative effects in the brain independent of its hematopoietic function. However, the specific role of EPO in modulating interneuron function and its contribution to restoring synaptic structures remains unclear.

Objective

To investigate how erythropoietin (rhEPO) affects hippocampal interneuron transcriptional networks, synaptic structures, and their role in the excitatory-inhibitory balance. The study aimed to identify distinct interneuron subtypes and determine molecular alterations upon rhEPO treatment that could explain its mitigation of neuropsychiatric disease phenotypes.

Results

Analysis resolved 15 transcriptionally distinct interneuron subtypes in the hippocampus. rhEPO treatment induced gene expression changes related to synaptic structure, trans-synaptic signaling, and metabolic pathways in a lineage-specific manner. Specific interneuronal populations exhibited reduced dendritic complexity, synaptic connectivity, and altered plasticity-related molecules, with compromised metabolism and inhibitory potential leading to greater excitability of pyramidal neurons.

Conclusion

Erythropoietin restrains the inhibitory potential of interneurons, particularly PVALB+ and SST+ populations, through alterations in their dendritic complexity, synaptic connectivity, and metabolic status. The improvement of neuropsychiatric phenotypes by rhEPO may partly result from this restrictive control over interneurons, which facilitates re-connectivity and synapse development of excitatory neurons and restoration of the excitatory-inhibitory balance.

Published in:Molecular Psychiatry,
Study Type:Experimental Research Study,
Source: PMID: 38622200, DOI: 10.1038/s41380-024-02528-2