In vivo MRI Successfully Reveals the Malformation of Cortical Development in Infant Rats

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), 1 H-MR spectroscopy, and diffusion tensor imaging, at postnatal day (P) 15 using a 7T smallanimal 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.

Multi-tensor diffusion abnormalities of gray matter in an animal model of cortical dysplasia

“…Toxic effects limit the application of Mn 2+ as an exogenous contrast in humans, thereby hampering its use for the diagnosis of FCD, and fostering the use of endogenous sources of contrast for the study of cortical layering. In a rodent model of FCD that shares similarities with the one used here ( 49 ) reductions of FA were found in white matter structures, as well as in the retrosplenial and cingulate cortices that are consistent with our findings ( Figure 3 ). In their study, alterations of cortical layering and hypomyelination were also identified.…”

Insulin-Like Growth Factor-1 Promotes Synaptogenesis Signaling, a Major Dysregulated Pathway in Malformation of Cortical Development, in a Rat Model

“…Quantitative proteome analysis revealed that synaptogenesis signaling was the most signi cantly downregulated canonical pathway in the malformed cortex of prenatal rats exposed to MAM at P15 (Table S1), consistent with the decrease in CaMKIIA along with an increase in the susceptibility to NMDAinduced spasms [5]. Our previous work demonstrated the poor dendritic spine development and reduced neuronal population in the RSC of prenatally MAM-exposed rats [12]. Altered early synaptogenesis is reported in neurodevelopmental disorders, including epilepsy, intellectual disability, and autism spectrum disorders [28].…”

“…In particular, the reduced activity of CaMKII is known to be related to epilepsy [31,32]. This decreased expression of cortical CaMKII in malformed brain may be related to the previously reported dendritic arborization [12] and increased spasm susceptibility [5].…”

“…The offspring from methylazoxymethanol (MAM)-treated rats have developmental brain anomalies, including migration failure, ventricular enlargement, and disorganization of neocortical and hippocampal structures [9,11], which resemble the pathologic ndings observed in patients with MCD [11,5]. Our previous studies have reported cognitive impairment and increased seizure susceptibility with increased fast oscillation (FO) as well as decreased dendritic arborization or cortical neurons during infancy in this MAM-induced MCD rat model [5] [12,13]. Using this MAM-induced MCD model [4,14], we aimed to identify the most severely deteriorated canonical pathway in the early postnatal period.…”

“…Hence, treatment is usually focused only on symptom relief or surgical resection of the dysplastic cortex. To identify the epileptogenetic mechanism of MCD, we conducted studies on a rat model using MAM and found clinical phenotypes similar to those in patients with MCD [5,12]. Using this model, we aimed to determine the major disrupted pathway in the MCD cortex.…”