The Pin1-CaMKII-AMPA Receptor Axis Regulates Epileptic Susceptibility

Abstract

Pin1 is a unique isomerase that regulates protein conformation and function after phosphorylation. Pin1 aberration contributes to some neurological diseases, notably Alzheimer’s disease, but its role in epilepsy is not fully understood. We found that Pin1-deficient mice had significantly increased seizure susceptibility in multiple chemical inducing models and developed age-dependent spontaneous epilepsy. Electrophysiologically, Pin1 ablation enhanced excitatory synaptic transmission to prefrontal cortex (PFC) pyramidal neurons without affecting their intrinsic excitability. Biochemically, Pin1 ablation upregulated AMPA receptors and GluA1 phosphorylation by acting on phosphorylated CaMKII. Clinically, Pin1 was decreased significantly, whereas phosphorylated CaMKII and GluA1 were increased in the neocortex of patients with epilepsy. Moreover, Pin1 expression restoration in the PFC of Pin1-deficient mice using viral gene transfer significantly reduced phosphorylated CaMKII and GluA1 and effectively suppressed their seizure susceptibility. Thus, Pin1-CaMKII-AMPA receptors are a novel axis controlling epileptic susceptibility, highlighting attractive new therapeutic strategies.

The role of peptidyl-prolyl isomerase Pin1 in neuronal signaling in epilepsy

“…The data strongly suggest the potential utility of Pin1 as a target for seizure protection (Hou et al, 2021). The function of Pin1 in epilepsy may be associated with some classical signaling pathways, such as the Notch1 signaling and PI3K/Akt signaling pathways.…”

“…The phosphorylation would reduce conformational heterogeneity and flexibility of the phosphobinding loop upon S16 phosphorylation and abrogates the binding capacity of Pin1 afterward, which would definitely affect the neuronal signaling in epilepsy (Luh et al, 2013;Smet-Nocca et al, 2013). Although there was no change in PKA in Pin1 10.3389/fnmol.2022.1006419 knockout mice (Hou et al, 2021), the underlying mechanism of mutual regulation between Pin1 and PKA is still worth further study.…”

“…These studies highlight the role of the V5a-Pin1 interaction in neural function. Although PKC showed no change in Pin1 KO mice (Hou et al, 2021), studies have shown the effect of Pin1 on the PKCα subunit (Abrahamsen et al, 2012). Thus, the interaction between PKC and Pin1 and its function and molecular mechanism in the development of epilepsy is urgently needed.…”

“…Specifically, Pin1 may be associated with excitatory glutamate receptors N-methyl-D-aspartic acid [(NMDA) receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] as well as inhibitory neurotransmitter receptors gamma-aminobutyric acid [(GABA) receptors and glycine receptors], which can effectively regulate the release of neurotransmitters and are significant in the progression of epilepsy. Electrophysiological studies of ion channels have also revealed some of the pathophysiological mechanisms underlying Pin1 and epilepsy ( Antonelli et al, 2014 , 2016 ; Hu J. H. et al, 2020 ; Hou et al, 2021 ).…”

Blocking ERK-DAPK1 Axis Attenuates Glutamate Excitotoxicity in Epilepsy

“…Mice were anesthetized and placed on a stereotaxic apparatus to implant epidural electroencephalogram (EEG) electrodes at the following positions (anteroposterior (AP), +2.0 mm, and mediolateral (ML), +1.5 mm) and a reference electrode (AP, −2.0 mm, and ML, +3.0) as described previously [ 42 , 65 ]. Video EEG recordings were taken of freely moving mice to trace seizure behaviors and obtain EEGs.…”