PIN1 and Epilepsy
There is a high rate of co-occurrence between autism and epilepsy, and many genetic defects are linked to both conditions [238,239]. Glyphosate has been shown to cause seizures in round worms, and this likely occurred through its action as a GABA-A receptor antagonist [240].
Recent studies reveal the role of PIN1 in the pathological development of a range of neurodegenerative diseases, which also includes a significant influence in the pathology of epilepsy. During epileptic seizures, an abnormal electrophysiology persists in the brain [241]. On the molecular level, the deregulation of synaptic transmissions is considered as a major contributing factor for epileptic seizures [242]. The balance of PIN1 isomerase activity would therefore be of importance for epilepsy, since it regulates the excitatory glutamate, N-methyl-D-aspartic acid (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the inhibitory gamma-aminobutyric acid (GABA) and glycine receptors. All these receptors are deregulated during epilepsy, as described in the Y Chen et al. study [243].
The acquisition of epileptic seizures in association with PIN1 deficiency has been observed in both animals and humans with impaired PIN1 function, suggesting that the expression of PIN1 can inhibit the symptoms of epilepsy [244]. PIN1 null mice have significantly increased susceptibility to seizures and develop age-dependent spontaneous epilepsy [245]. Recent studies in animals show that PIN1 deficiency increases the susceptibility to epileptic seizures upon chemical stimuli. Moreover, in humans with epilepsy, PIN1 is significantly downregulated whereas AMPA receptors are overactive. PIN1 deficient mice have a significantly increased risk to seizures, and humans with epilepsy have increased phosphorylation of CaMKII and increased levels of AMPA receptors in the neocortex. PIN1 knockout increases the number of AMPA receptors through hyperphosphorylation of CaMKII [245]. In animal experiments, CaMKII hyperphosphorylation is reversed by the restoration of PIN1 expression in the prefrontal cortex of their brains [245]. Social impairments in animal models of autism can be ameliorated by antagonists of the AMPA receptors [246]. These studies suggest that PIN1 upregulation can restore proper neural network function and cortical synaptic organization in epilepsy.