Vascular endothelial growth factor‐C modulates cortical NMDA receptor activity in cortical lesions of young patients and rat model with focal cortical dysplasia

Abstract

Emergence of dysmorphic neurons is the primary pathology in focal cortical dysplasia (FCD) associated pediatric intractable epilepsy; however, the etiologies related to the development and function of dysmorphic neurons are not fully understood. Our previous studies revealed that the expression of vascular endothelial growth factor‐C (VEGF‐C) and corresponding receptors VEGFR‐2, VEGFR‐3 was increased in the epileptic lesions of patients with tuberous sclerosis complex or mesial temporal lobe epilepsy. Here, we showed that the expression of VEGF‐C, VEGFR‐2, and VEGFR‐3 was increased at both mRNA and protein levels in patients with cortical lesions of type I, IIa, and IIb FCD. The immunoreactivity of VEGF‐C, VEGFR‐2 and VEGFR‐3 was located in the micro‐columnar neurons in FCD type I lesions, dysplastic neurons (DNs) in FCD type IIa lesions, balloon cells (BCs) and astrocytes in FCD type IIb lesions. Additionally, the amplitude of evoked‐EPSCs (eEPSC) mediated by NMDA receptor, the ratio of NMDA receptor‐ and AMPA receptor‐mediated eEPSC were increased in the dysmorphic neurons of FCD rats established by prenatal X‐ray radiation. Furthermore, NMDA receptor mediated current in dysmorphic neurons was further potentiated by exogenous administration of VEGF‐C, however, could be antagonized by ki8751, the blocker of VEGFR‐2. These results suggest that VEGF‐C system participate in the pathogenesis of cortical lesions in patients with FCD in association with modulating NMDA receptor–mediated currents.

Balloon cells in malformations of cortical development: friends or foes?

“…Additionally, the generalized anabolic activity resulting from mTOR hyperactivity may promote the nonspecific production of immune factors [113]. Meanwhile, Yang et al investigated the link between inflammatory responses and BCs in FCD and TSC tissues, providing evidence that supports the role of BCs in initiating inflammatory response [81,82,85,114]. In their studies, he and colleagues first observed the overexpression of interleukins and their receptors (IL-6/IL-6R, IL-17/IL-17) in BCs in FCD IIb, which were co-expressed with GFAP and sometimes with NF200 [81].…”

“…Specifically, TLR-2 was predominantly detected in microglia/macrophage cells and BCs, indicating that they represented a significant source of pro-inflammatory molecules [77]. Secondly, increased levels of VEGFs were found in BCs, DNs and astrocytes in FCD IIb, which could contribute to astroglial activation and associated inflammatory reactions [65,82]. Furthermore, high levels of MMP9 were detected in BCs and reactive astrocytes, which is known to be a regulator of various physiological and pathological inflammatory processes [83].…”

Expression profiles of α-synuclein in cortical lesions of patients with FCD IIb and TSC, and FCD rats

“…The other three control cortical specimens were obtained from individuals who were diagnosed with increased intracranial pressure due to traumatic brain injury and without any neurological disease in history. The samples distant from the directly injured area were obtained in <6h after brain injury (33) after comprehensive presurgical assessment, including history, neuroimaging studies, and neurological examination according to the criteria (27,34). The detailed information of each control subject is shown in Supplementary Table S3.…”

“…Additionally, Vimentin is generally used as a marker of immature glia and neurons during development (36) and was also used as a maker for BCs traditionally, which were demonstrated to be immature neurons in FCD lesions (37)(38)(39)(40). However, GFAP is commonly used as a mature astrocytic marker (41, 42) and rarely detected in BCs in FCD lesions (27,43,44).…”

“…More importantly, rats are closer to humans with less genomic differences and greater physiological similarities in consequence, making them the ideal and classical animal for constructing FCD models (23-26), whereas chemical or physical stimulation-induced mouse models of FCD have been rarely reported. In the study, we used in utero irradiation of pregnant rats to X-ray to generate FCD rats in consistent with the procedures used in our previous study (27). Striking the loss of normal six-layered cortex, varying degrees of cytomegalic or dysmorphic cells and spontaneous seizures were reported in these animals (9,28,29).…”