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2000). on phosphorylated CaMKII. Clinically, Pin1 was decreased significantly, whereas phosphorylated CaMKII and GluA1 were increased in the neocortex of Biricodar dicitrate (VX-710 dicitrate) 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. and conformations after they are phosphorylated on specific Ser or Thr residues preceding a Pro residue (pSer/Thr-Pro) (Lu et?al. 1996; Kozono et?al. 2018; Nechama et?al. 2018; Chen et?al. 2019). Pin1 is now known to have a profound impact on many key proteins involved in diverse cellular processes (Lu 2004; Lu and Zhou 2007; Lee et?al. 2011; Liou et?al. 2011). Pin1 aberrations contribute to many diseases, notably Alzheimers disease (AD), and thus, Pin1 has become an attractive novel drug target for controlling the deregulation of protein conformations (Lu 2004; Driver et?al. 2015). Interestingly, recent studies have shown that Pin1 specifically catalyzes phosphorylated tau from the pathogenic and conformation-specific antibodies (Lu et?al. 2016). Recently, it was reported that the expression of Pin1 is downregulated in the brain tissue of patients with temporal lobe epilepsy (Tang et?al. 2017). However, the role and mechanisms of Pin1 in epileptogenesis are still unknown. It is well known that the central nervous system networks of synaptically connected excitatory glutamatergic neurons are critical in generating epileptic synchronization. The fast synaptic excitation predominantly mediated by AMPA receptors is especially important. AMPA receptor antagonists markedly reduce or abolish epileptiform activity in a broad range of animal seizure models, which suggests that AMPA receptors are crucial to epileptic discharges (Rogawski 2013). More recently, evidence from clinical trials that perampanel has acceptable safety and significant efficacy in the treatment of human partial-onset seizures validates the AMPA receptor as a novel target for epilepsy therapy (French et?al. 2013). A key mediator of AMPA receptors is calcium/calmodulin-dependent protein kinase II (CaMKII), which is strongly expressed at excitatory synapses. CaMKII activity can drive AMPA receptors to synapses by a mechanism that requires their GluA1 subunit (Hayashi et?al. 2000). Itgal GluA1 is phosphorylated by CaMKII at Ser831, and such phosphorylation may enhance the conductance of AMPA receptors (Derkach et?al. 1999; Kristensen et?al. 2011). A recent study found that Pin1 bound to phosphorylated CaMKII and weakened its activity (Shimizu et?al. 2018). Therefore, we speculate that Pin1 might interact with CaMKII to affect AMPA receptors associated with epilepsy. Here, we used multiple chemical inducing models of epilepsy to investigate seizure susceptibility in 2003). Open in a separate window Figure 2 The morphology and intrinsic excitability of pyramidal neurons in the PFC were unchanged in Pin1 KO Biricodar dicitrate (VX-710 dicitrate) mice. (and was similar in both genotypes. (2017). More Biricodar dicitrate (VX-710 dicitrate) importantly, we found that GluA1 phosphorylated at Ser831 and CaMKII phosphorylated at Thr286 were both increased in the human neocortex tissues of patients with epilepsy, as we observed in Pin1 KO mice. However, the total level of AMPA receptors did not change significantly (Fig. 62016), chronic traumatic encephalopathy (Albayram et?al2016), Parkinson disease (Ryo et?al. 2006; Ghosh et?al. 2013), amyotrophic lateral sclerosis (Kesavapany et?al. 2007), and Huntingtons disease (Grison et?al. 2011). Pin1 is inactivated in the hippocampus of patients with mild cognitive impairment and AD (Butterfield et al. 2006; Sultana et?al. 2006). Pin1 knockout causes mice to develop diffuse phenotypes of premature aging similar to AD in humans (Lee et?al. 2009; Driver et?al. 2014). Transgenic overexpression of Pin1 in postnatal neurons in mice is able to protect against age-dependent neurodegeneration (Lim et?al. 2008). A recent study in an epileptic mouse model reported evidence that seizure activity downregulates Pin1 expression levels (Tang et?al. 2017). In the present study, Pin1 KO mice displayed severe induced seizures and age-dependent spontaneous epilepsy, indicating that endogenous Pin1 acts as an inhibitor during epileptogenesis. All of these studies suggest that Pin1 has strong neuroprotective effects. The expression levels of Pin1 vary widely in different tissues. Pin1 is downregulated in cells that are not proliferating. In contrast, Pin1 is highly expressed in neurons from the beginning of neuronal differentiation (Becker and Bonni 2006; Hamdane et?al. 2006). Pin1 immunoreactivity is mainly distributed in hippocampal and cortical pyramidal neurons in human brains (Dakson et?al. 2011). In agreement with these studies, we observed Pin1 immunofluorescence in PFC pyramidal neurons according to colocalization with NeuN, a.