The Amyloid Precursor Protein Regulates Synaptic Transmission at Medial Perforant Path Synapses

Area of Science:

• Neuroscience
• Synaptic Plasticity
• Molecular Biology

Background:

• The perforant path is the primary excitatory input to the hippocampus, crucial for information processing.
• Understanding synaptic transmission between entorhinal cortex (EC) stellate cells and dentate gyrus (GC) neurons is vital.
• The perforant path is significantly affected in Alzheimer's disease.

Purpose of the Study:

• To characterize synaptic transmission between individual EC-GC neuron pairs.
• To compare EC-GC synapse properties from lateral and medial entorhinal cortex afferents.
• To investigate the role of amyloid precursor protein (APP) in EC-GC synaptic function, particularly in the context of Alzheimer's disease.

Main Methods:

• Used mouse organotypic entorhino-hippocampal tissue cultures.
• Employed whole-cell patch-clamp recordings to study EC-GC pairs.
• Utilized wild-type and APP-deficient mouse models, including conditional APP deletion via viral vectors.

Main Results:

• Identified differences in short-term plasticity between lateral and medial EC inputs.
• APP deficiency altered excitatory neurotransmission at medial perforant path synapses, with associated transcriptomic and ultrastructural changes.
• Presynaptic APP deletion enhanced neurotransmission efficacy at perforant path synapses.

Conclusions:

• Presynaptic APP plays a physiological role in limiting excitatory neurotransmission at medial perforant path synapses.
• Altered APP processing conditions may adversely affect perforant path synaptic function.
• Findings suggest a mechanism by which APP impacts hippocampal function relevant to Alzheimer's disease.