Erythropoietin restrains the inhibitory potential of interneurons in the mouse hippocampus
Por:
Curto Y, Carceller H, Klimczak P, Perez-Rando M, Wang Q, Grewe K, Kawaguchi R, Rizzoli S, Geschwind D, Nave K, Teruel-Marti V, Singh M, Ehrenreich H, Nácher J
Publicada:
1 oct 2024
Ahead of Print:
1 abr 2024
Resumen:
Severe psychiatric illnesses, for instance schizophrenia, and affective diseases or autism spectrum disorders, have been associated with cognitive impairment and perturbed excitatory-inhibitory balance in the brain. Effects in juvenile mice can elucidate how erythropoietin (EPO) might aid in rectifying hippocampal transcriptional networks and synaptic structures of pyramidal lineages, conceivably explaining mitigation of neuropsychiatric diseases. An imminent conundrum is how EPO restores synapses by involving interneurons. By analyzing similar to 12,000 single-nuclei transcriptomic data, we generated a comprehensive molecular atlas of hippocampal interneurons, resolved into 15 interneuron subtypes. Next, we studied molecular alterations upon recombinant human (rh)EPO and saw that gene expression changes relate to synaptic structure, trans-synaptic signaling and intracellular catabolic pathways. Putative ligand-receptor interactions between pyramidal and inhibitory neurons, regulating synaptogenesis, are altered upon rhEPO. An array of in/ex vivo experiments confirms that specific interneuronal populations exhibit reduced dendritic complexity, synaptic connectivity, and changes in plasticity-related molecules. Metabolism and inhibitory potential of interneuron subgroups are compromised, leading to greater excitability of pyramidal neurons. To conclude, improvement by rhEPO of neuropsychiatric phenotypes may partly owe to restrictive control over interneurons, facilitating re-connectivity and synapse development.
Filiaciones:
Curto Y:
Max Planck Inst Multidisciplinary Sci, Clin Neurosci, City Campus, Gottingen, Germany
Univ Valencia, Program Neurosci, Neuroplast Unit, Burjassot, Spain
Univ Valencia, Inst Biotechnol & Biomed BIOTECMED, Burjassot, Spain
Carceller H:
Univ Valencia, Program Neurosci, Neuroplast Unit, Burjassot, Spain
Univ Valencia, Inst Biotechnol & Biomed BIOTECMED, Burjassot, Spain
Spanish Natl Network Res Mental Hlth CIBERSAM, Madrid, Spain
Fdn Invest Hosp Clin Valencia INCLIVA, Valencia, Spain
Klimczak P:
Univ Valencia, Program Neurosci, Neuroplast Unit, Burjassot, Spain
Univ Valencia, Inst Biotechnol & Biomed BIOTECMED, Burjassot, Spain
Spanish Natl Network Res Mental Hlth CIBERSAM, Madrid, Spain
Fdn Invest Hosp Clin Valencia INCLIVA, Valencia, Spain
Perez-Rando M:
Univ Valencia, Program Neurosci, Neuroplast Unit, Burjassot, Spain
Univ Valencia, Inst Biotechnol & Biomed BIOTECMED, Burjassot, Spain
Spanish Natl Network Res Mental Hlth CIBERSAM, Madrid, Spain
Fdn Invest Hosp Clin Valencia INCLIVA, Valencia, Spain
Wang Q:
Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA USA
Grewe K:
Univ Med Ctr Gottingen, Dept Neuro & Sensory Physiol, Gottingen, Germany
Kawaguchi R:
Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA USA
Rizzoli S:
Univ Med Ctr Gottingen, Dept Neuro & Sensory Physiol, Gottingen, Germany
Geschwind D:
Univ Calif Los Angeles, Inst Precis Hlth, Los Angeles, CA USA
Nave K:
Max Planck Inst Multidisciplinary Sci, Dept Neurogenet, City Campus, Gottingen, Germany
Teruel-Marti V:
Univ Valencia, Dept Anat & Human Embryol, Neuronal Circuits Lab, Valencia, Spain
Singh M:
Max Planck Inst Multidisciplinary Sci, Clin Neurosci, City Campus, Gottingen, Germany
Ehrenreich H:
Max Planck Inst Multidisciplinary Sci, Clin Neurosci, City Campus, Gottingen, Germany
Georg August Univ, Gottingen, Germany
Heidelberg Univ, Cent Inst Mental Hlth, Med Fac Mannheim, Dept Psychiat & Psychotherapy,Expt Med, J 5, Mannheim, Germany
Nácher J:
Univ Valencia, Program Neurosci, Neuroplast Unit, Burjassot, Spain
Univ Valencia, Inst Biotechnol & Biomed BIOTECMED, Burjassot, Spain
Spanish Natl Network Res Mental Hlth CIBERSAM, Madrid, Spain
Fdn Invest Hosp Clin Valencia INCLIVA, Valencia, Spain
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