A Tuber-ful Animal Model of Tuberous Sclerosis At Last?

Commentary Tuberous sclerosis complex (TSC) is one of the most common genetic etiologies of epilepsy. Epilepsy in TSC patients may involve multiple seizure types and is often intractable to medication. TSC is caused by mutation of either the TSC1 or TSC2 gene and is characterized pathologically by the development of hamartomas or tumors in multiple organs. Cortical tubers, hamartomatous lesions of the brain, are most closely associated with epilepsy and other neurologic symptoms of TSC, such as autism and developmental delay. Tubers represent focal cortical malformations, consisting of loss of normal cortical lamination, dysmorphic neurons, astrogliosis, and unique giant cells with immature neuronal and glial features. The importance of tubers in causing seizures is supported by the fact that surgical removal of tubers can eliminate seizures in a subset of TSC patients (1). Direct pathologic analysis of tubers resected from TSC patients during epilepsy surgery has provided abundant information about the histologic, cellular, and molecular features of these lesions. However, the specific mechanisms of epilepto-genesis and seizure generation (ictogenesis) in TSC continue to be poorly understood. First, it's often debated as to whether seizures originate from within the tubers themselves or the surrounding perituberal cortex. Although traditionally tubers were assumed to generate seizures directly, recent invasive electrical recordings from TSC patients suggest that epilepti-form activity primarily arises from the periturberal regions (2). Other unresolved issues include defining the relative involvement of aberrant networks (tuberal or perituberal), abnormal cell types (e.g., giant cells, dysmorphic neurons, astrogliosis), and molecular defects (e.g., abnormal glutamate or GABA receptor expression) in promoting epileptogenesis and seizure generation. In addition, the role of abnormal activation of the mTOR pathway, the major biochemical pathway regulated by the TSC genes, in triggering various downstream mechanisms of epileptogenesis is under intense investigation. A number of animal models of TSC have been developed that have yielded insights into the pathophysiology of neurologic manifestation of TSC, including epilepsy. Several of these rodent models, involving inactivation of either the Tsc1 or Tsc2 gene in various subsets of brain cells, have recapitulated some of the cellular aspects of human tubers, such as dysmorphic or cytomegalic neurons and astrogliosis (3–5). Furthermore, some models have identified novel molecular defects, such as in astrocyte glutamate transporters, that likely relate to epileptogenesis and have subsequently been confirmed in human tubers (3, 6). However, despite these advances, a major criticism of existing animal models of TSC is the failure …