Inhibiting 5-HT_2C receptor in the hippocampus rescues EphB2-dependent memory impairment in mice

EphB2 is a tyrosine kinase receptor that regulates key neuronal functions such as synaptic transmission and morphogenesis. EphB2 dysfunction is associated with neurological disorders and dementia. In Alzheimer's disease, EphB2 depletion leads to memory deficits in mouse models, and its level is reduced in patients. EphB2 expression also declines with aging. Moreover, EphB2 dysfunction has been linked to autism. Here, we show that long-term memory (LTM) of auditory fear conditioning is impaired in EphB2^lacZ/lacZ male mice that lack EphB2 forward signaling. However, LTM was significantly increased when we microinjected the 5-HT_2C serotonin receptor antagonist SB 242084 into the hippocampus before fear memory retrieval. SB 242084 microinjection before testing did not affect freezing in EphB2^lacZ/lacZ when mice were exposed to the tone per se during training and testing. The 5-HT_2C antagonist did not affect fear LTM in wild-type mice. SB 242084 was ineffective when injected before fear conditioning training. Microinjection of the 5-HT_2C receptor agonist MK-212 into the hippocampus of wild-type mice before memory retrieval did not affect LTM. We further revealed that SB 242084 altered the intrinsic properties of pyramidal hippocampal neurons leading to increased excitability only in EphB2^lacZ/lacZ but not in wild-type mice. The results show that memory is not lost in EphB2^lacZ/lacZ mice but rather memory is inaccessible and can be recovered with 5-HT_2C antagonists. Furthermore, it may be possible to rescue such memory impairments in brain diseases where EphB2 dysfunction is involved.