Clinical NeuroscienceReviewGenetic animal models of malformations of cortical development and epilepsy

- Genetic animal models mimic the spectrum of human malformations of cortical development.
- Advanced genetic methods have engineered increasingly sophisticated animal models of cortical malformations.
- Distinct and overlapping mechanisms of epileptogenesis occur across different animal models of cortical malformations.
- Animal models have identified novel therapeutic targets for epilepsy, such as the mTOR pathway.

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.