Pin1 Modulates the Synaptic Content of NMDA Receptors via Prolyl-Isomerization of PSD-95

Abstract

Our data indicate that Pin1 controls synaptic content of NMDARs via PSD-95 prolyl-isomerization and the expression of dendritic spines, both required for LTP maintenance.

Pin1 mediates Aβ 42 -induced dendritic spine loss

“…Unexpectedly, germ-line Pin1 KO cortex tissues exhibit increased dendritic spine density and increased LTP in hippocampal slices (6, 10). To clarify these seemingly contradictory results, we measured total dendritic spine density of primary DIV21 Pin1 fl/fl neurons after transfection on DIV7 with Td-tomato and either NLS-GFP (WT) or NLS-GFP-Cre (KO) (fig S1A).…”

Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses

“…Furthermore, conflicting results are observed as to the role of Pin1 in the regulation of post-synaptic spines between the global KO (Antonelli et al, 2016) and the conditional KO (Stallings et al, 2018). For instance, the global Pin1 knockout mice show an increase in spine density (Antonelli et al, 2016) while a recent paper shows that deleting Pin1 from the adult hippocampus decreases it Stallings et al (2018). These discrepancies in results, led us to reevaluate the role for post-synaptic Pin1 in dendritic spine morphology.…”

“…The decrease in PSD-95 palmitoylation and number of PSD-95 clusters suggests that Pin1 could regulate dendritic spines because PSD-95 palmitoylation strongly regulates dendritic spine formation (El-Husseini et al, 2000. Furthermore, conflicting results are observed as to the role of Pin1 in the regulation of post-synaptic spines between the global KO (Antonelli et al, 2016) and the conditional KO (Stallings et al, 2018). For instance, the global Pin1 knockout mice show an increase in spine density (Antonelli et al, 2016) while a recent paper shows that deleting Pin1 from the adult hippocampus decreases it Stallings et al (2018).…”

“…To confirm the effects of Pin1 on NMDAR currents as in Antonelli et al (2016), NMDAR-mediated transmission was evaluated on by isolating single spine miniature NMDAR (mNMDARs) events by using a modified ACSF containing 0 mM Mg 2+ , 1 µM TTX, and 10 µM DNQX. Ca 2+ entry through the NMDAR was imaged using the high-affinity Ca 2+ sensor GCaMP6S in a spinning disk microscopy (see Materials and Methods" and Supplementary Movie I).…”

Whole genome bisulfite sequencing of Down syndrome brain reveals regional DNA hypermethylation and novel disorder insights

“…In contrast, hypomethylated DS-DMRs were enriched for glial immune processes and proline isomerization ( Figure 5). Proline isomerization is a regulatory signaling switch with functions that span glutamatergic signaling 28 and epigenetic modifications of the histone H3 tail that influence H3K4me3 29 and H3K36me3 30 levels, which are two modifications found to be significantly enriched within hypomethylated DS-DMRs ( Figure 3B). The significant (p<0.05) canonical pathways enriched for hypermethylated DS-DMRs were primarily related to glutamatergic signaling, while hypomethylated DS-DMRs were enriched for antigen presentation and apoptosis ( Figure 5).…”