The Role of Ephs and Ephrins in Memory Formation

Abstract

The ability to efficiently store memories in the brain is a fundamental process and its impairment is associated with multiple human mental disorders. Evidence indicates that long-term memory formation involves alterations of synaptic efficacy produced by modifications in neural transmission and morphology. The Eph receptors and their cognate ephrin ligands have been shown to be involved in these key neuronal processes by regulating events such as presynaptic transmitter release, postsynaptic glutamate receptor conductance and trafficking, synaptic glutamate reuptake, and dendritic spine morphogenesis. Recent findings show that Ephs and ephrins are needed for memory formation in different organisms. These proteins participate in the formation of various types of memories that are subserved by different neurons and brain regions. Ephs and ephrins are involved in brain disorders and diseases with memory impairment symptoms, including Alzheimer’s disease and anxiety. Drugs that agonize or antagonize Ephs/ephrins signaling have been developed and could serve as therapeutic agents to treat such diseases. Ephs and ephrins may therefore induce cellular alterations mandatory for memory formation and serve as a target for pharmacological intervention for treatment of memory-related brain diseases.

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

“…Our results explicitly delineated that EPHB2 is the most significant altered molecule of Ephrin receptor signaling in the hypothalamus of the LPS-induced depressive phenotype. EPHB2 is not only involved in glutamatergic neurotransmission but also simultaneously participates in the inflammation regulation process in some brain diseases including stroke, anxiety and Alzheimer's disease (Coulthard et al, 2012;Dines and Lamprecht, 2016;Ernst et al, 2019). Cumulatively, our present study and aforementioned studies showed that EPHB2 is intimately involved in inflammationrelated depression.…”

“…mediates glutamatergic neurotransmission and neuroplasticity in injury and inflammation of the CNS (Coulthard et al, 2012;Wan et al, 2018). 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).…”

“…Additionally, the acute phase response signaling, often presented in depressed patients (Wang et al, 2018), was also shown in the present LPS depression model. The most important is Ephrin receptor signaling, as the fourth top-ranked statistically canonical pathways in the bi-omics, which regulates neuroinflammation and nervous system development through mediating glutamatergic neurotransmission, and neuroplasticity (Dines and Lamprecht, 2016;Wan et al, 2018). Given several key proteins within the pathway, such as Ephrin-B1 (EFNB1) and EPHB2, Ephrin receptor signaling may participate in inflammation-associated depression.…”

Coding and non-coding RNA dysregulation in bipolar disorder

“…The Eph receptor belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. Eph receptors and ephrins (their ligands) regulate key CNS processes, such as neurotransmitter release, postsynaptic glutamate receptor conductance, synaptic glutamate reuptake, and dendritic spine morphogenesis 48 . They are involved in memory formation 49 and anxiety 50 .…”

“…Memory deficits (during episodes and interepisodic) and high anxiety levels (during episodes) are both often reported in BPD. It is therefore of interest that Ephs and ephrins (their ligands) may be pharmacologically targeted 48,51,52 : EphB2-blockade impedes physiological stress responses in wild-type mice 50 . In addition to serving as therapeutic targets, traces of RNAs may serve as markers to monitor disease progression, as has been demonstrated for cancer 47 .…”