Genetic animal models of malformations of cortical development and epilepsy

Abstract

Malformations of cortical development constitute a variety of pathological brain abnormalities that commonly cause severe, medically-refractory epilepsy, including focal lesions, such as focal cortical dysplasia, hetereotopias, and tubers of tuberous sclerosis complex, and diffuse malformations, such as lissencephaly. Although some cortical malformations result from environmental insults during cortical development in utero, genetic factors are increasingly recognized as primary pathogenic factors across the entire spectrum of malformations. Genes implicated in causing different cortical malformations are involved in a variety of physiological functions, but many are focused on regulation of cell proliferation, differentiation, and neuronal migration. Advances in molecular genetic methods have allowed the engineering of increasingly sophisticated animal models of cortical malformations and associated epilepsy. These animal models have identified some common mechanistic themes shared by a number of different cortical malformations, but also revealed the diversity and complexity of cellular and molecular mechanisms that lead to the development of the pathological lesions and resulting epileptogenesis.

Early rescue of interneuron disease trajectory in developmental epilepsies

“…A second important take home message is that seizures may be separable from structural circuit abnormalities. For example, some genes produce striking brain malformations such as cortical dyslamination in the double cortex syndrome ( DCX ), or prominent balloon cells and tubers of tuberous sclerosis ( TSC1 ), however, mouse models show that these structural defects are not essential for epilepsy to occur [26,42]. Thus partial phenotypic rescue, that is preventing seizures, may be possible even in the face of major brain malformations.…”

“…Gene-linked migration disorders include lissencephaly, subcortical band heterotopia/double cortex syndrome, and focal cortical dysplasias [25,26]. Deletions in the LIS1 gene (OMIM 607432 ) and a microdeletion that encompasses LIS1 (Miller-Dieker Syndrome) are causes of lissencephaly and often have severe, intractable epilepsy appearing early in life [27].…”

“…Doublecortin ( DCX ) (OMIM 300121 ) is located on the X-chromosome and DCX missense mutations are a common cause of X-linked lissencephaly and subcortical band heterotopia, with a high incidence of epilepsy [26,36]. DCX encodes a microtubule-associated protein expressed in migrating neurons and involved in microtubule stabilization [37].…”

Altered Electroencephalography Spectral Profiles in Rats with Different Patterns of Experimental Brain Dysplasia

“…The etiology of brain malformations is generally linked to disturbed prenatal or early postnatal development, in particular, impaired neurogenesis or neuronal migration (Barkovich et al, ). The molecular and cellular mechanisms leading to the development of malformations of cortical development (MCD) are studied with different animal models addressing distinct subtypes or aspects of FCD (Luhmann, ; Wong and Roper, ). Despite these developments, there is still an ongoing need for refinement (Pitkänen et al, ).…”

“…It is proposed that the loss of migrating neuroblasts and radial glial cells underlies the generation of dysplasia in this model (Wong and Roper, ). What follows from this assumption, is the anticipation of different time points of irradiation giving rise to distinct “patterns” of dysplasia.…”