Amyloid--Induced Dendritic Spine Elimination Requires Ca²⁺-Permeable AMPA Receptors AKAP-Calcineurin-NFAT Signaling and the NFAT Target Gene Mdm2

Alzheimer's disease (AD) is associated with brain accumulation of synaptotoxic amyloid-beta (A beta) peptides produced by the proteolytic processing of amyloid precursor protein (APP). Cognitive impairments associated with AD correlate with dendritic spine and excitatory synapse loss, particularly within the hippocampus. In rodents, soluble A beta oligomers (A beta o) impair hippocampus-dependent learning and memory, promote dendritic spine loss, inhibit NMDA-type glutamate receptor (NMDAR)-dependent long-term potentiation (LTP), and promote synaptic depression (LTD), at least in part through activation of the Ca2+-CaM-dependent phosphatase calcineurin (CaN). Yet, questions remain regarding A beta-dependent postsynaptic CaN signaling specifically at the synapse to mediate its synaptotoxicity. Here, we use pharmacologic and genetic approaches to demonstrate a role for postsynaptic signaling via A kinase-anchoring protein 150 (AKAP150)-scaffolded CaN in mediating A beta -induced dendritic spine loss in hippocampal neurons from rats and mice of both sexes. In particular, we found that Ca2+-permeable AMPA-type glutamate receptors (CP-AMPARs), which were previously shown to signal through AKAP-anchored CaN to promote both LTD and A beta-dependent inhibition of LTP, are also required upstream of AKAP-CaN signaling to mediate spine loss via overexpression of APP containing multiple mutations linked to familial early-onset AD (FAD) and increased A beta production. In addition, we found that the CaN-dependent nuclear factor of activated T-cells (NFAT) transcription factors is required downstream to promote A beta-mediated dendritic spine loss. Finally, we identified the E3-ubiquitin ligase Mdm2, which was previously linked to LTD and developmental synapse elimination, as a downstream NFAT target gene upregulated by A beta whose enzymatic activity is required for AR-mediated spine loss.