Erythropoietin restrains the inhibitory potential of interneurons in the mouse hippocampus

Cognitive impairment and disturbed excitatory-inhibitory balance in the brain have been linked to severe psychiatric illnesses such as schizophrenia, affective disorders, and autism spectrum disorders. Erythropoietin (EPO) may have a role in mitigating them by rectifying hippocampal transcriptional networks and synaptic architectures of pyramidal lineages when administered to juvenile mice. How EPO involves interneurons to rebuild synapses is an impending puzzle. After examining ~12,000 single-nuclei transcriptomic data, we generated a comprehensive molecular atlas of hippocampal interneurons, resolved into 15 subtypes. By analyzing molecular alterations upon recombinant human (rh)EPO, we observed changes in gene expression associated with synaptic structure, trans-synaptic signaling and intracellular catabolic pathways. In addition, rhEPO significantly altered potential ligand-receptor interactions between inhibitory and pyramidal neurons, which regulates synaptogenesis. Numerous in/ex vivo studies demonstrated that particular interneuronal populations reduced their dendritic complexity and synaptic connectivity, accompanied by changes in plasticity-related molecules. A compromised metabolism and inhibitory potential of certain interneuronal subtypes, render pyramidal neurons more excitable. In conclusion, tight control over interneurons, which facilitates re-connectivity and synapse formation, may contribute to the amelioration of neuropsychiatric symptoms by rhEPO.