Activation Of PDK1-AKT-mTOR Pathway In Characteristic Balloon Cells And Dysmorphic Neurons Of Type Ⅱ Focal Cortical Dysplasia With Refractory Epilepsy

Objectives:To investigate wether PDK1-AKT-mTOR signaling pathway is abnormallyactivated in the various types of focal cortical dysplasia (FCD) with refractoryepilepsy, and to define whether the characteristic balloon cells and dysmorphicneurons of typeⅡ focal cortical dysplasia with refractory epilepsy exhibitdifferential PDK1-AKT-mTOR signaling pathway.Methods:Surgically resected specimens, which pathology diagnosed as FCD,frompatients with medically intractable epilepsy treated at the neurosurgerydepartment of the First Affiliated Hospital of Fujian Medical University between2007and2010were retrospectively chosen for this study from archival paraffinblocks. These include tissue in the following group categories:（Ⅰ）FCD ⅡB (n=4)；（Ⅱ） FCD ⅡA(n=8)；（Ⅲ） FCD Ⅰ(n=8).Normal-appearing cortexsadjacent to dysplastic lesions obtained from FCD patients in group Ⅰ，ⅡandⅢ were classified as epilepsy control specimens（n=8）, Histologically normalneocortex obtained from the frontal lobe brain tissue which is inevitably to beremoved in surgical approach in the patient of lateral ventricle tumor withoutepilepsy as a blank control group(n=3). we investigated immunocytochemicallythe expression of phosphorylated p-PDK1(Ser241)、 p-AKT(Thr308)、 p-AKT(Ser473)、p-mTOR(Ser2448)、p-P70S6K(Thr229)、p-P70S6K(Thr389)in above brian tissue specimens and compared with the control group.Results:①Only a few of pyramidal neurons in control group (perilesional neocortex andhistologically normal neocortex) displayed weak p-PDK1(Ser241)、p-AKT(Thr308)、p-AKT(Ser473)、p-mTOR(Ser2448)、p-P70S6K(Thr229)、p-P70S6K(Thr389) immunoreactivity （IR）,Varying degrees of moderatepositive or strong positive p-PDK1(Ser241), p-AKT(Thr308), p-AKT(Ser473),p-mTOR(Ser2448),p-P70S6K(Thr229), p-P70S6K (Thr389) staining wereobserved in the characteristic balloon cells and dysmorphic neurons of typeⅡFCD. p-PDK1(Ser241)、p-AKT(Thr308) staining in BCs were stronger than inDNs，p-P70S6K(Thr229)、p-P70S6K(Thr389) staining in BCs were weakerthan in DNs，and there are no differences in between p-AKT(Ser473)、p-mTOR(Ser2448) staining in DNs and in BCs.②Expressions of p-PDK1(Ser241), p-AKT (Thr308), p-AKT (Ser473), p-of mTOR (Ser2448),p-P70S6K(Thr229), the p-P70S6K (Thr389) in FCD I type lesions were negative.Conclusions:Abnormal activation of PDK1-AKT-mTOR signaling pathway in characteristicballoon cells and dysmorphic neurons of typeⅡ focal cortical dysplasia withrefractory epilepsy may be an important molecular mechanism of thehistological changes and repeated seizures.Both DNs and BCs have the same PDK1-AKT-mTOR pathway activation mayindicates they have the common pathogenic origins, and differences in somecompnents may have to do with cell-specific gene expression.Differences in activation of the PDK1-AKT-mTOR signaling pathway indicatesthat FCD I and FCD II may have different pathogenic mechanisms.