Abstract
Astrocytes play a fundamental role in synapse formation, pruning, and plasticity, which are associated with learning and memory. However, the role of astrocytes in learning and memory is still largely unknown. Our previous study showed that astrocyte-specific ephrin-B1 knock-out (KO) enhanced but ephrin-B1 overexpression (OE) in hippocampal astrocytes impaired contextual memory recall following fear conditioning. The goal of this study was to understand the mechanism by which astrocytic ephrin-B1 influences learning; specifically, learning-induced remodeling of synapses and dendritic spines in CA1 hippocampus using fear-conditioning paradigm. While we found a higher dendritic spine density and clustering on c-Fos-positive (+) neurons activated during contextual memory recall in both wild-type (WT) and KO mice, overall spine density and mEPSC amplitude were increased in CA1 neurons of KO compared to WT. In contrast, ephrin-B1 OE in hippocampal astrocytes impaired dendritic spine formation and clustering, specifically on c-Fos(+) neurons, coinciding with an overall decrease in vGlut1/PSD95 co-localization. Although astrocytic ephrin-B1 influenced learning-induced spine formation, the changes in astrocytic ephrin-B1 levels did not affect spine enlargement as no genotype differences in spine volume were observed between trained WT, KO, and OE groups. Our results suggest that a reduced formation of new spines rather than spine maturation in activated CA1 hippocampal neurons is most likely responsible for impaired contextual learning in OE mice due to abundantly high ephrin-B1 levels in astrocytes. The ability of astrocytic ephrin-B1 to negatively influence new spine formation during learning can potentially regulate new synapse formation at specific dendritic domains and underlie memory encoding.
Highlights
Hippocampal circuits are known for their plastic nature and play an important role in the formation of new memories and life-long learning (Milner et al, 1998; Neves et al, 2008)
While we found that both wild-type (WT) and astrocytic ephrin-B1 knock-out (KO) mice showed a significant increase in dendritic spine density and clustering on activated c-Fos(+) neurons compared to c-Fos(-) neurons following contextual recall, dendritic spine density remained higher in trained KO compared to WT, which coincided with a greater vesicular glutamate transporter 1 (vGlut1)/postsynaptic density-95 (PSD95) co-localization and enhanced excitatory postsynaptic currents (EPSCs) in CA1 neurons of KO mice
We previously reported that the loss of astrocytic ephrin-B1 in adult mice resulted in enhanced contextual recall, while OE of ephrin-B1 in the adult hippocampal astrocytes impaired contextual memory recall (Koeppen et al, 2018)
Summary
Hippocampal circuits are known for their plastic nature and play an important role in the formation of new memories and life-long learning (Milner et al, 1998; Neves et al, 2008). Contextual fear learning and retrieval relies on the hippocampus, the CA1 region. This hippocampaldependent learning requires activation of CA1 pyramidal neurons (Strekalova et al, 2003; Goshen et al, 2011), and promotes the growth and maturation of hippocampal synapses. In addition to promoting synapse maturation, experience has been shown to modify hippocampal circuits through selective formation or removal of synapses (Lichtman and Colman, 2000; Draft and Lichtman, 2009; Holtmaat and Svoboda, 2009; Sala and Segal, 2014; Segal, 2017). Most research has focused on neuron– neuron interactions; little is known about astrocytederived signals that regulate the synaptic remodeling during learning and memory
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