Erythropoietin Stimulates GABAergic Maturation in the Mouse Hippocampus
Kasifa Khalid1,2, Julia Frei1, Mostafa A Aboouf3
1Institute of Pharmacology and Toxicology, Neuroprotection Group, University of Zurich, Zurich 8057, Switzerland.
Insights
Erythropoietin (EPO) promotes the development of the GABAergic system in the hippocampus, enhancing neuronal survival and synaptic transmission. This finding supports EPO
Area of Science:
- Neuroscience
- Developmental Biology
- Neuropharmacology
Background:
- GABAergic transmission is crucial for neurodevelopment; its dysfunction is linked to various neurodevelopmental disabilities.
- Current therapies to normalize GABAergic development are limited.
- Erythropoietin (EPO) is used in neonatology for brain injury and neuronal maturation, but its effect on the GABAergic system is unknown.
Purpose of the Study:
- To investigate whether EPO can stimulate the maturation of the GABAergic system during postnatal development.
- To explore the underlying mechanisms of EPO's potential effects on GABAergic development in the hippocampus.
Main Methods:
- Utilized a transgenic mouse line (Tg21) with constitutive neuronal EPO overexpression.
- Assessed GABAergic neuron markers, interneuron populations (PV, SST, NPY), perineuronal net (PNN) formation, and synaptic function (IPSCs).
- Examined EPO receptor (EPOR) expression and apoptosis in hippocampal cells.
Main Results:
- Tg21 mice showed increased hippocampal GABA-immunoreactive neurons and elevated expression of PV, SST, and NPY interneurons.
- Enhanced PNN formation and glutamatergic innervation onto PV+ cells were observed early postnatally.
- Increased GABAAergic synapse density and IPSCs in CA1 pyramidal cells were detected in Tg21 mice.
- EPOR mRNA was localized to glutamatergic pyramidal cells and increased in Tg21 mice, with reduced apoptosis.
Conclusions:
- EPO significantly stimulates postnatal GABAergic maturation in the hippocampus.
- EPO enhances GABAergic development by promoting neuronal survival, modulating plasticity, and increasing synaptic transmission.
- These findings suggest EPO as a potential therapeutic agent for GABAergic dysfunction in neurodevelopmental disorders.
Abstract:
Several neurodevelopmental disabilities are strongly associated with alterations in GABAergic transmission, and therapies to stimulate its normal development are lacking. Erythropoietin (EPO) is clinically used in neonatology to mitigate acute brain injury, and to stimulate neuronal maturation. Yet it remains unclear whether EPO can stimulate maturation of the GABAergic system. Here, with the use of a transgenic mouse line that constitutively overexpresses neuronal EPO (Tg21), we show that EPO stimulates postnatal GABAergic maturation in the hippocampus. We show an increase in hippocampal GABA-immunoreactive neurons, and postnatal elevation of interneurons expressing parvalbumin (PV), somatostatin (SST), and neuropeptide Y (NPY). Analysis of perineuronal net (PNN) formation and innervation of glutamatergic terminals onto PV+ cells, shows to be enhanced early in postnatal development. Additionally, an increase in GABAAergic synapse density and IPSCs in CA1 pyramidal cells from Tg21 mice is observed. Detection of EPO receptor (EPOR) mRNA was observed to be restricted to glutamatergic pyramidal cells and increased in Tg21 mice at postnatal day (P)7, along with reduced apoptosis. Our findings show that EPO can stimulate postnatal GABAergic maturation in the hippocampus, by increasing neuronal survival, modulating critical plasticity periods, and increasing synaptic transmission. Our data supports EPO's clinical use to balance GABAergic dysfunction.
