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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• EphB2 receptor tyrosine kinase is crucial for neuronal functions like synaptic transmission and morphogenesis.
• EphB2 dysfunction is implicated in neurological disorders, including Alzheimer's disease and autism, often associated with memory deficits and reduced expression with aging.
• EphB2 depletion in mouse models of Alzheimer's disease causes memory impairment.

Purpose of the Study:

• To investigate the role of EphB2 forward signaling in long-term memory (LTM) of auditory fear conditioning.
• To explore the potential of targeting 5-HT2C serotonin receptors to rescue memory deficits in EphB2-deficient mice.

Main Methods:

• Auditory fear conditioning and long-term memory testing in EphB2 mutant (EphB2^lacZ/lacZ) and wild-type mice.
• Hippocampal microinjection of the 5-HT2C antagonist SB 242084 or agonist MK-212 before memory retrieval or training.
• Electrophysiological analysis of hippocampal pyramidal neuron excitability.

Main Results:

• EphB2^lacZ/lacZ mice exhibited impaired LTM for auditory fear conditioning.
• Microinjection of SB 242084 into the hippocampus rescued LTM in EphB2^lacZ/lacZ mice without affecting freezing to the tone alone.
• SB 242084 treatment increased hippocampal pyramidal neuron excitability specifically in EphB2^lacZ/lacZ mice.
• The 5-HT2C antagonist was ineffective when administered before training or in wild-type mice, and the agonist MK-212 did not affect LTM in wild-type mice.

Conclusions:

• Memory deficits in EphB2^lacZ/lacZ mice are due to inaccessibility rather than loss.
• Targeting 5-HT2C serotonin receptors can restore inaccessible fear memory.
• This finding offers a potential therapeutic strategy for memory impairments associated with EphB2 dysfunction in brain diseases.