Synaptic plasticity regulated by phosphorylation of PSD-95 Serine 73 in dorsal CA1 is required for contextual fear extinction

Abstract

The ability to update and extinguish fearful memories is essential for survival. Accumulating data indicate that the dorsal CA1 area (dCA1) contributes to this process. However, the cellular and molecular basis of fear memory updating remains poorly understood. Postsynaptic density protein 95 (PSD-95) regulates the structure and function of glutamatergic synapses. Here, we investigated the role of dCA1 PSD-95-driven synaptic plasticity in contextual fear extinction. Using dCA1-targeted genetic manipulations in vivo combined with PSD-95 immunostaining and 3D electron microscopy ex vivo, we demonstrate that phosphorylation of PSD-95 at serine 73 PSD-95(S73) is necessary for contextual fear extinction-induced expression of PSD-95 and remodeling of glutamatergic synapses. Surprisingly, PSD-95 phosphorylation is not necessary for fear memory formation or early extinction but is required for updating a partly extinguished fear memory, affecting its persistence. Using a chemogenetic manipulation, we confirm that updating of the partly extinguished fear requires PSD-95 expression and dCA1 activity during a prior extinction session. Overall, our data indicate that dCA1 synapses are remodeled upon the extinction of contextual fear memories; this process relies on PSD-95(S73) phosphorylation and enables future updating of a partly extinguished contextual fear memory. These findings show how the hippocampus may contribute to the persistence of fear memories.