Abstract
Receptor tyrosine kinase EphB2 mediates development of the neurogenic niche of excitatory neurons, suggesting the possibility that its inactivation plays a role in neuropsychiatric disorders including depression and memory impairment. While N-methyl-D-aspartate (NMDA) receptor is involved in regulating memory formation and neurogenesis in adult animal, it remains unclear how NMDA receptor subtypes mediate depression and cognitive deficits caused by EphB2 loss. The present study shows that EphB2 inactivation results in depression-like behaviors, memory impairment and defects of adult hippocampal neurogenesis. Compared to wild-type littermates, EphB2 KO mice exhibited depression-like behavior and deficits in spatial memory and cognition in forced swimming, tail suspension, Morris water maze, object recognition test and object location test. These behavioral abnormalities were accompanied by substantial decreases in the number of BrdU+ progenitor neurons, phosphorylation of cAMP-response element binding protein (pCREB) and brain derived neurotrophic factor (BDNF), and increased NMDA receptor 2B (NR2B) expression. These molecular, cellular and behavioral alterations induced by EphB2 inactivation were reversed by NR2B antagonist Ro25-6981, suggesting that EphB2 functions to prevent the progression of depression-like behavior and memory impairment by downregulating NR2B. Our findings highlight that NR2B is responsible for EphB2-dependent behavioral and morphological changes. EphB2 may thus be as an important candidate target for treating psychiatric and cognitive disorders.
Highlights
The Eph family of receptor tyrosine kinases is subdivided into EphA and EphB receptors, based on their ability to bind two subclasses of cognate ligands, ephrinAs or ephrinBs, respectively (Himanen and Nikolov, 2003)
We examined whether EphB2 inactivation changes the expression or activity status of proteins that are downstream of the NMDA receptor 2B
We show that EphB2 plays an important role in depressionlike behaviors, cognitive and memory impairment by inactivating the gene using a knockout approach
Summary
The Eph family of receptor tyrosine kinases is subdivided into EphA and EphB receptors, based on their ability to bind two subclasses of cognate ligands, ephrinAs or ephrinBs, respectively (Himanen and Nikolov, 2003). At least four members of the Eph receptor family including EphA4, EphB1, EphB2, and EphB3 are highly expressed in the prefrontal cortex, hippocampus and amygdala, whose functions are closely related to emotional and cognitive disorders, such as depression, anxiety, and memory deficits (Liebl et al, 2003). Depression is generally accompanied by cognitive and memory deficits, which are critical determinants of functional outcomes in patients with major depressive disorders (Jaeger et al, 2006). It is not well understood how does loss of EphB2 mediate depression and associated cognitive deficits
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