Conditional deletion of Eps8 reduces hippocampal synaptic plasticity and impairs cognitive function

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Epidermal growth factor receptor substrate 8 (Eps8) is a key regulator of the actin cytoskeleton.
• Eps8 is highly expressed in the brain, but its specific functions in neuronal plasticity and cognition are not well understood.

Purpose of the Study:

• To investigate the role of Eps8 in cognitive function and hippocampal synaptic plasticity.
• To elucidate the underlying molecular mechanisms, particularly the involvement of N-methyl-d-aspartate receptors (NMDARs).

Main Methods:

• Generated Eps8 knockout (Eps8-/-) mice with genetic deletion in excitatory neurons.
• Assessed cognitive performance using the novel object recognition test.
• Performed electrophysiological recordings in hippocampal slices to measure long-term potentiation (LTP) and NMDAR-mediated currents.
• Analyzed dendritic spine morphology and NMDAR subunit expression.

Main Results:

• Eps8-/- mice exhibited impaired performance in the novel object recognition test.
• A deficit in LTP maintenance was observed in hippocampal CA1 neurons of Eps8-/- mice, which was rescued by NMDAR antagonist.
• Enhanced NMDAR-mediated excitatory postsynaptic currents (EPSCs) with slower decay kinetics were detected in Eps8-/- neurons.
• Eps8 deletion resulted in decreased mature dendritic spine density but increased basal dendritic tree complexity.

Conclusions:

• Eps8 plays a critical role in regulating hippocampal long-term synaptic plasticity and cognitive function.
• NMDAR hyperfunction contributes to the cognitive deficits observed in Eps8-/- mice.
• Eps8 influences neuronal structure, including dendritic spine density and dendritic complexity.