The Role of Paroxysmal Depolarization Shifts in Epilepsy

The term epilepsy represents an umbrella term for a variety of diseases of the central nervous system, which are characterized by the spontaneous recurrence of simultaneous electrical discharge activity. This abnormal recurrent activity is denoted as an epileptic seizure, and is accompanied by more or less severe signs and symptoms, depending on its spatial and temporal distribution. Accordingly, quality of life may mildly to severely be impaired by this disease. It has become possible in a majority of patients to prevent epileptic seizures with therapeutic drugs, or - in case of insufficiency - by surgical ablation of the affected brain tissue. However, rather than to secondarily suppress seizures it would be superior to prevent the development of the entire epileptic condition right at the start of pathogenesis. Unfortunately, this is still not possible to date. Many forms of epilepsy emerge early on in life, and are typically due to genetic mutations. Therapeutic intervention with the pathogenic mechanisms, which can be envisaged to initiate already in utero, remains difficult to achieve. Having said that, a hitherto less appreciated fraction of epilepsies begins only later in life, often after the age of 50. These epilepsies are referred to as acquired forms, because they develop after injuries of the brain or as a consequence of dysfunction of the aging brain. This project aims at elucidating pathomechanisms of acquired epilepsies, the knowledge of which may then serve to develop prophylactic therapeutic approaches. Research in this project will focus on very particular electric signals of nerve cells, which have become known under the term PDS. Circumstantial evidence suggested that PDS were crucially involved in the initiation or some early steps of epileptogenesis. However, controversy exists among epileptologists regarding the actual role of PDS, whether they may be part of an attempt of nerve cells to prevent further damage or whether they may directly be responsible for seizure- causing changes. We will address this question in vitro with experiments on neurons dissociated from rat brain and maintained under culture conditions. Our results shall help to clarify, whether prevention of PDS can be envisaged to be beneficial, or whether on the contrary, suppression of PDS may worsen the course of the disease. In previous work we have already obtained a detailed understanding of the ionic nature of PDS. For example, we identified the flux of calcium ions via the neuronal cell membrane as a crucial component of PDS formation. Hence, blockade of this flux of Ca2+ with a specific calcium channel inhibitor will allow us to put to the test the impact of PDS suppression in vivo in a mouse model of epileptogenesis.