Volume 19, Issue 2

Mechanisms of genetic epilepsies. Epilepsy is one of the most common neurological disorders. Already at the time of Hippocrates (460 - 370 BC) it was reported on as the “holy disease” (Fröscher 2004). Today it is known that an epileptic seizure is a consequence of synchronous discharges of neuronal populations in the brain, which abruptly and usually without an observ­able cause evoke involuntary behavioural dysfunction or impaired consciousness. Epilepsies can have various causes and lead to extensive implications for the everyday life of affected patients. Up to 50 % of all epilepsies are caused by genetic defects, in particular the so-called idiopathic epilepsies which occur without easily observable structural alterations of the brain. Genetically caused dysfunctions of neuronal ion channels play a central role in the formation of such epilepsies. The ion channels control the ion flux over the cell membrane of neurons and thus present the basis for the excitability of these neurons. Therefore, medications used for epilepsy treatment affect predominantly ion channels. However, the common anticonvulsants have limited success, not only because one third of epilepsy patients exhibits pharmacoresistance, but also because of the secondary effects which can dramatically affect their quality of life. Furthermore, current therapeutic approaches are mainly symptomatic and do not act on the epileptogenic mechanisms which are still largely unknown. In this review article we will highlight the current main topics of our research on genetically caused epilepsies, their pathomechanisms and therapeutic options.

Neuronal networks in the spotlight: deciphering cellular activity patterns with fluo­rescent proteins. The brain’s astounding achievements regarding movement control and sensory pro­cessing are based on complex spatiotemporal activity patterns in the relevant neuronal networks. Our understanding of neuronal network activity is, however, still poor, not least because of the experimental difficulties to directly observe neural circuits at work in the living brain (in vivo). Over the last decade, new opportunities have emerged - especially utilizing 2-photon microscopy - to investigate neuronal networks in action. Central to this progress was the development of fluorescent proteins that change their emission depending on cell activity, enabling the visualization of dynamic activity pat­terns in local neuronal populations. Currently, genetically encoded calcium indicators, proteins which indicate neuronal activity based on action potential-evoked calcium influx, are becoming increasingly used. Long-term expression of these indicators allows repeated monitoring of the same neurons over weeks and months, such that stability and plasticity of their functional properties can be characterized. Furthermore, permanent indicator expression facilitates the correlation of cellular activity patterns and behavior in awake animals. Using examples from recent studies of information processing in mouse neocortex, we review in this article these fascinating new possibilities and discuss the great potential of fluorescent proteins to elucidate the mysteries of neural circuits.

The art of forging neurons: direct reprogramming of somatic cells into induced neu­ronal cells. Cellular reprogramming has shed new light on the plasticity of terminally differentiated cells and discloses novel strategies for cell-based therapies for neurological disorders. With accumulating knowledge of the programs underlying the genesis of the distinct neural cell types, especially with the identification of relevant transcription factors and microRNAs, reprogramming of somatic cells of different origins into induced neuronal cells or neural stem cells has been successfully achieved. Starting with the general con­cept of reprogramming we discuss here three different paradigms: 1) direct conversion of CNS-foreign cells such as skin fibroblasts into induced neuronal cells or neural stem cells; 2) transdifferentiation of CNS resident cells such as astrocytes and brain pericytes into induced neuronal cells; 3) reprogramming of one neuronal subtype into another. The latter has already been successfully achieved in vivo during early brain develop­ment, providing strong impulse for the attempt to succeed in direct reprogramming in situ for future brain repair.

Epilepsy is one of the most common neuro­logical disorders. As early as the time of Hip­pocrates (460-370 BC), it was reported on as the “holy disease”. Today it is known that an epileptic seizure is a consequence of synchro­nous discharges of neuronal populations in the brain, which abruptly and usually without an observable cause evoke involuntary be­havioural dysfunction or impaired conscious­ness. Epilepsies can have various causes and lead to extensive implications for the every­day life of affected patients. Up to 50% of all epilepsies are caused by genetic defects, in particular the so-called idiopathic epilep­sies, which occur without easily observable structural alterations in the brain. Genetical­ly caused dysfunctions of neuronal ion chan­nels play a central role in the formation of such epilepsies. The ion channels control the ion flux over the cell membrane of neurons and thus present the basis for the excitabili­ty of these neurons. Therefore, medications used in epilepsy treatment affect predomi­nantly ion channels. However, common an­ticonvulsants have limited success, not only because one third of epilepsy patients exhibit pharmacoresistance, but also because of the secondary effects which can dramatically af­fect their quality of life. Furthermore, current therapeutic approaches are mainly symp­tomatic and do not act on the epileptogenic mechanisms, which are still largely unknown. In this review article we will highlight the cur­rent main topics of our research on genetical­ly caused epilepsies, their pathomechanisms and therapeutic options.

The brain’s astounding achievements regard­ing movement control and sensory process­ing are based on complex spatiotemporal ac­tivity patterns in the relevant neuronal net­works. Our understanding of neuronal net­work activity is, however, still poor, not least because of the experimental difficulties in di­rectly observing neural circuits at work in the living brain (in vivo). Over the last decade, new opportunities have emerged-especial­ly utilizing two-photon microscopy-to in­vestigate neuronal networks in action. Cen­tral to this progress was the development of fluorescent proteins that change their emis­sion depending on cell activity, enabling the visualization of dynamic activity patterns in local neuronal populations. Currently, genet­ically encoded calcium indicators, proteins that indicate neuronal activity based on ac­tion potential-evoked calcium influx, are be­ing increasingly used. Long-term expression of these indicators allows repeated moni­toring of the same neurons over weeks and months, such that the stability and plastici­ty of their functional properties can be char­acterized. Furthermore, permanent indicator expression facilitates the correlation of cel­lular activity patterns and behavior in awake animals. Using examples from recent studies of information processing in the mouse neo­cortex, we review in this article these fasci­nating new possibilities and discuss the great potential of the fluorescent proteins to eluci­date the mysteries of neural circuits.

Cellular reprogramming has shed new light on the plasticity of terminally differentiated cells and unearthed novel strategies for cell-based therapies to treat neurological disor­ders. With accumulating knowledge of the programs underlying the genesis of the dis­tinct neural cell types, particularly the iden­tification of crucial transcription factors and microRNAs, reprogramming of somatic cells of different origins into induced neuronal cells or neural stem cells has been success­fully achieved. Starting with the general con­cept of reprogramming, we discuss three dif­ferent paradigms: (1) direct conversion of central nervous system (CNS) foreign cells such as skin fibroblasts into induced neuro­nal cells or neural stem cells; (2) transdiffer­entiation of CNS resident cells such as astro­cytes and brain pericytes into induced neuro­nal cells; (3) reprogramming of one neuronal subtype into another. The latter has already been successfully achieved in vivo during ear­ly brain development, providing a strong im­pulse to attempt direct reprogramming in si­tu for future brain repair.