Functional Consequences of Synapse Remodeling Following Astrocyte-Specific Regulation of Ephrin-B1 in the Adult Hippocampus

Abstract

Astrocyte-derived factors can control synapse formation and functions, making astrocytes an attractive target for regulating neuronal circuits and associated behaviors. Abnormal astrocyte-neuronal interactions are also implicated in neurodevelopmental disorders and neurodegenerative diseases associated with impaired learning and memory. However, little is known about astrocyte-mediated mechanisms that regulate learning and memory. Here, we propose astrocytic ephrin-B1 as a regulator of synaptogenesis in adult hippocampus and mouse learning behaviors. We found that astrocyte-specific ablation of ephrin-B1 in male mice triggers an increase in the density of immature dendritic spines and excitatory synaptic sites in the adult CA1 hippocampus. However, the prevalence of immature dendritic spines is associated with decreased evoked postsynaptic firing responses in CA1 pyramidal neurons, suggesting impaired maturation of these newly formed and potentially silent synapses or increased excitatory drive on the inhibitory neurons resulting in the overall decreased postsynaptic firing. Nevertheless, astrocyte-specific ephrin-B1 knock-out male mice exhibit normal acquisition of fear memory but enhanced contextual fear memory recall. In contrast, overexpression of astrocytic ephrin-B1 in the adult CA1 hippocampus leads to the loss of dendritic spines, reduced excitatory input, and impaired contextual memory retention. Our results suggest that astrocytic ephrin-B1 may compete with neuronal ephrin-B1 and mediate excitatory synapse elimination through its interactions with neuronal EphB receptors. Indeed, a deletion of neuronal EphB receptors impairs the ability of astrocytes expressing functional ephrin-B1 to engulf synaptosomes Our findings demonstrate that astrocytic ephrin-B1 regulates long-term contextual memory by restricting new synapse formation in the adult hippocampus. These studies address a gap in our knowledge of astrocyte-mediated regulation of learning and memory by unveiling a new role for ephrin-B1 in astrocytes and elucidating new mechanisms by which astrocytes regulate learning. Our studies explore the mechanisms underlying astrocyte regulation of hippocampal circuit remodeling during learning using new genetic tools that target ephrin-B signaling in astrocytes On a subcellular level, astrocytic ephrin-B1 may compete with neuronal ephrin-B1 and trigger astrocyte-mediated elimination of EphB receptor-containing synapses. Given the role EphB receptors play in neurodevelopmental disorders and neurodegenerative diseases, these findings establish a foundation for future studies of astrocyte-mediated synaptogenesis in clinically relevant conditions that can help to guide the development of clinical applications for a variety of neurological disorders.

Astrocytic Ephrin-B1 Controls Synapse Formation in the Hippocampus During Learning and Memory

“…There were no detectable changes in ephrin-B1 levels in astrocytes or neurons of TAM-injected WT mice (not shown). In TAM-treated KO mice, ephrin-B1 immunoreactivity was observed only in neuronal cell bodies and dendrites of the CA1 hippocampus, but was significantly reduced in hippocampal astrocytes as previously reported (Nikolakopoulou et al, 2016;Koeppen et al, 2018). Genotypes were confirmed by PCR analysis of genomic DNA isolated from mouse tails.…”

“…However, little is known about the role of astrocytic ephrin-B1. We previously reported that deletion and overexpression (OE) of astrocytic ephrin-B1 in the adult CA1 hippocampus affects contextual memory (Koeppen et al, 2018), but the mechanism is still not clear.…”

Perturbation of Ephrin Receptor Signaling and Glutamatergic Transmission in the Hypothalamus in Depression Using Proteomics Integrated With Metabolomics

“…The Eph tyrosine kinase receptors were subdivided into 9 EPHA receptors (EPHA1-8 and EPHA10) and 5 EPHB receptors (EPHB1-4 and EPHB6), based on their binding to two subclasses of cognate ligands, Ephrin-As and Ephrin-Bs (Dines and Lamprecht, 2016;Taylor et al, 2017). The EPHB/Ephrin-Bs, which are distributed extensively and provide unique bidirectional signaling between neurons and astrocytes, have attracted considerable attention because of their regulation of neuronal maturation and synaptic plasticity (Koeppen et al, 2018). Dysfunction of EPHB2 and its ligand EFNB1 has been implicated in brain disorders, such as cognition disorders and depression (Zhang et al, 2016;Koeppen et al, 2018).…”

“…The EPHB/Ephrin-Bs, which are distributed extensively and provide unique bidirectional signaling between neurons and astrocytes, have attracted considerable attention because of their regulation of neuronal maturation and synaptic plasticity (Koeppen et al, 2018). Dysfunction of EPHB2 and its ligand EFNB1 has been implicated in brain disorders, such as cognition disorders and depression (Zhang et al, 2016;Koeppen et al, 2018). Even in other subtypes of depression animal models, EPHB2 was preliminarily found to regulate neuronal development, NMDAR function, and synaptic plasticity of the hippocampus and PFC (Zhang et al, 2016;Zhen et al, 2018).…”

Compartment-Specific Neurexin Nanodomains Orchestrate Tripartite Synapse Assembly

“…SPARCL1, thrombospondin-1, Chordin-like 1, TGFβ, and glypicans), the molecular mechanisms utilized by astrocytes to instruct synapse formation and to regulate synapse function are largely unknown (Allen et al, 2012;Blanco-Suarez et al, 2018;Christopherson et al, 2005;Diniz et al, 2012;Kucukdereli et al, 2011;Nagal et al, 2019). Recent studies have implicated cell-adhesion molecules expressed by astrocytes, such as neuroligins and Ephrin-B1, in regulating synapse formation (Koeppen et al, 2018;Stogsdill et al, 2019). However, the extent to which astrocytes employ these or other cell adhesion molecules to regulate synaptic information processing remains unclear (Bohmback et al, 2018;Durkee et al, 2019;Farhy-Tsenlnicker et al, 2018;Papouin et al, 2017).…”