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, heterotopias, 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.

Keywords: Focal cortical dysplasia; Heterotopia; Lissencephaly; Mice; Seizure; Tuberous sclerosis.

Figure 1

The mTOR pathway as a central signaling pathway causing malformations of cortical development and epilepsy. The mTOR pathway involves two complexes, the rapamycin-sensitive, mTORC1, and the relatively rapamycin-insensitive, mTORC2 (not shown), is regulated by a number of upstream signaling pathways, and controls many important downstream functions, including cell growth and proliferation. Genetic mutations in different components of the mTOR pathway have been identified that cause abnormal activation of mTORC1 and may lead to various malformations of cortical development and epilepsy syndromes involving increased cell growth and proliferation (blue). Inhibition of mTORC1 by rapamycin or other mTORC1 inhibitors may represent a rational therapy for epilepsy and malformations of cortical development due to abnormal mTOR pathway activation. AMPK - 5' adenosine monophosphate-activated protein kinase; DEPDC5 - Dishevelled, Egl-10 and Pleckstrin domain-containing protein 5; FCD - focal cortical dysplasia; MCD - malformation of cortical development; FFEVF - familial focal epilepsy with variable foci; GATOR1 - GTPase-activating protein activity towards Rags; mTORC1 - mammalian target of rapamycin complex 1; NPRL2 - nitrogen permease regulator 2-like protein; NPRL3 - nitrogen permease regulator 3-like protein; PI3K - phosphoinositide-3 kinase; PMSE - polyhydramnios, megalencephaly, symptomatic epilepsy; PTEN - phosphatase and tensin homolog on chromosome 10; Rheb - Ras homolog enriched in brain; STRADα - STE20-related kinase adapter alpha; TSC1 - tuberous sclerosis complex 1 protein; TSC2 - tuberous sclerosis complex 2 protein.