Nanoarchitecture of CaV2.1 channels and GABAB receptors in the mouse hippocampus: Impact of APP/PS1 pathology.

Voltage-gated Ca_V2.1 (P/Q-type) Ca²⁺ channels play a crucial role in regulating neurotransmitter release, thus contributing to synaptic plasticity and to processes such as learning and memory. Despite their recognized importance in neural function, there is limited information on their potential involvement in neurodegenerative conditions such as Alzheimer's disease (AD). Here, we aimed to explore the impact of AD pathology on the density and nanoscale compartmentalization of Ca_V2.1 channels in the hippocampus in association with GABA_B receptors. Histoblotting experiments showed that the density of Ca_V2.1 channel was significantly reduced in the hippocampus of APP/PS1 mice in a laminar-dependent manner. Ca_V2.1 channel was enriched in the active zone of the axon terminals and was present at a very low density over the surface of dendritic tree of the CA1 pyramidal cells, as shown by quantitative SDS-digested freeze-fracture replica labelling (SDS-FRL). In APP/PS1 mice, the density of Ca_V2.1 channel in the active zone was significantly reduced in the strata radiatum and lacunosum-moleculare, while it remained unaltered in the stratum oriens. The decline in Cav2.1 channel density was found to be associated with a corresponding impairment in the GABAergic synaptic function, as evidenced by electrophysiological experiments carried out in the hippocampus of APP/PS1 mice. Remarkably, double SDS-FRL showed a co-clustering of Ca_V2.1 channel and GABA_B1 receptor in nanodomains (~40-50 nm) in wild type mice, while in APP/PS1 mice this nanoarchitecture was absent. Together, these findings suggest that the AD pathology-induced reduction in Ca_V2.1 channel density and Ca_V2.1-GABA_B1 de-clustering may play a role in the synaptic transmission alterations shown in the AD hippocampus. Therefore, uncovering these layer-dependent changes in P/Q calcium currents associated with AD pathology can benefit the development of future strategies for AD management.