Abstract
Objective: Malformations of cortical development (MCDs) are major causes of intractable epilepsies. To characterize the early neuroimaging findings of MCDs, we tried to identify the MRI features consistent with pathological findings in an infant rat MCD model, prenatally exposed to methylazoxymethanol (MAM), by using newly developed MRI techniques.Methods: At gestational day 15, two doses of MAM (15 mg/kg intraperitoneally) or normal saline were injected into pregnant rats. The offspring underwent in vivo MRI, including glutamate chemical exchange saturation transfer (GluCEST), 1H-MR spectroscopy, and diffusion tensor imaging, at postnatal day (P) 15 using a 7T small-animal imaging system. Another set of prenatally MAM-exposed rats were sacrificed for histological staining.Results: At P15, the retrosplenial cortex (RSC) of rats with MCDs showed decreased neuronal nuclei, parvalbumin, and reelin expressions. Moreover, dendritic arborization of pyramidal cells in the RSC significantly decreased in infant rats with MCDs. In vivo MRI showed significantly decreased GluCEST (%) in the RSC of rats with MCDs (p = 0.000) and a significant correlation between GluCEST (%) and RSC thickness (r = 0.685, p = 0.003). The rats with MCDs showed reduced glutamate (p = 0.002), N-acetylaspartate (p = 0.002), and macromolecule and lipid levels (p = 0.027) and significantly reduced fractional anisotropy values in the RSC.Conclusion: In vivo MRI revealed reduced neuronal population and dendritic arborization in the RSC of infant rats with MCDs during the early postnatal period. These pathological changes of the cortex could serve as clinical imaging biomarkers of MCDs in infants.
Highlights
The cerebral cortex is composed of six layers of glutamatergic and inhibitory interneurons (Kwan et al, 2012)
Primary antibodies [anti-MBP, a marker for myelinatin, 1: 500; anti-TBR1, for layer VI neurons; 1: 250, and anti-parvalbumin, for GABAergic neurons, 1: 500; Abcam, Cambridge, United Kingdom; anti-MAP2, for neuronal dendrites, 1: 1,000; anti-neuronal nuclei (NeuN), for neurons, 1: 500, and anti-reelin, for neuronal migration, 1: 1,000; EMD Millipore, MA, United States] with blocking solution were applied for 24 h at 4◦C, and fluorescein-labeled secondary antibodies [fluorescein anti-mouse immunoglobulin G (IgG), fluorescein anti-rabbit IgG, and Cy R 3 anti-rabbit IgG, Vector Laboratories; Alexa Fluor 594 anti-rat IgG, Thermo Fisher Scientific] were serially applied for 1 h at room temperature
Cresyl violet staining showed collapsed cortical structures in infant rats prenatally exposed to MAM (Figure 3A)
Summary
The cerebral cortex is composed of six layers of glutamatergic and inhibitory interneurons (Kwan et al, 2012). The migration of these neurons into the proper layer of the cerebral cortex is an essential process during early cortical development, and its disruption causes malformations of cortical development (MCDs). In clinical settings, localization of MCDs for epilepsy surgery is not always possible with current imaging techniques, especially in infants or in individuals with small focal cortical dysplasia (FCD). Non-invasive imaging diagnosis of FCD is important to offer the right therapeutic option to patients with intractable focal epilepsies (Jayalakshmi et al, 2019)
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