Postsynaptic target specific synaptic dysfunctions in the CA3 area of BACE1 knockout mice

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Beta-amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme in amyloid-beta (Aβ) production, a hallmark of Alzheimer's disease (AD).
• Complete BACE1 gene ablation prevents Aβ formation but can lead to presynaptic deficits in BACE1 knockout (KO) mice.
• Previous studies noted mossy fiber (MF) to CA3 synapse deficits in BACE1 KO mice, but postsynaptic target specificity was unclear.

Purpose of the Study:

• To investigate whether synaptic deficits in BACE1 KO mice are specific to postsynaptic targets within the CA3 region.
• To compare the effects of BACE1 deficiency on CA3 pyramidal cells (PYR) and stratum lucidum (SL) interneurons, both receiving MF inputs.

Main Methods:

• Whole-cell electrophysiological recordings were performed in CA3 PYRs and SL interneurons of BACE1 KO and wild-type mice.
• Paired-pulse facilitation (PPF) was assessed at MF inputs to both cell types.
• Miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) were analyzed in CA3 PYRs and SL interneurons.

Main Results:

• BACE1 KO mice exhibited enhanced PPF at MF inputs to CA3 PYRs but not SL interneurons, indicating postsynaptic target specificity.
• Synaptic dysfunction extended to inhibitory synapses onto CA3 PYRs, with increased PPF of evoked inhibitory postsynaptic currents.
• A reduction in mEPSC and mIPSC frequencies was observed in CA3 PYRs, but not SL interneurons, suggesting a global impairment in CA3 PYRs.

Conclusions:

• Synaptic dysfunctions in BACE1 KO mice are specific to the postsynaptic CA3 pyramidal cells, irrespective of the input type.
• These findings highlight the critical role of BACE1 in maintaining normal synaptic function in specific neuronal populations, beyond its role in Aβ production.