Transregional Research Centre Mesial Temporal Lobe Epilepsies (SFB/TR3)
General Introduction
Funded by the Deutsche Forschungsgemeinschaft (Link)1st funding period: July 2001 - June 2004 - grant: € 6.12 Mio. (3 years)
2nd funding period: July 2004 - June 2008 - grant: € 9.05 Mio. (4 years, announced)
1 Significance of mesial temporal lobe epilepsy (TLE)
2 The molecular and cellular mechanisms underlying mesial TLE – Research objectives of the consortium I
3 Mesial TLE as a model disease to study functional plasticity and cognition in the human brain - Research objectives of the consortium II
4 Long-term goals of the research project
5 Need for an interdisciplinary consortium in the field of epilepsy research
6 Scope of the interdisciplinary research consortium: Sections within the transregional SFB
Epilepsy is one of the most prevalent neurological diseases affecting approximately 600,000 people in Germany. Epilepsy comprises a large number of syndromes, which vary greatly with respect to their symptomatology, clinical course, treatment and prognosis. However, all these syndromes share a characteristic manifestation: recurrent spontaneous seizures as a chronic condition. An epileptic seizure is a sudden, highly synchronized electrical discharge of neurons, which may occur in virtually every cortical area of the brain, and which disrupts normal brain function for 60 to 90 seconds during the seizure and, more subtle, up to hours in the so called postictal phase. Recurring seizures have devastating behavioral, social and occupational consequences. They may additionally damage the brain and increase pre-existing neurological deficits. Unfortunately, current anticonvulsant drugs and complementary therapeutic methods are not sufficient to control seizures in about a third of the epileptic patients. Moreover, some patients cannot tolerate the side effects of the drugs or develop pharmacological resistance. Thus, there is an urgent need for treatments that prevent the development of epilepsy and control it better in patients already inflicted with the disease.
In the last decade or two, tremendous advances in different fields of the neurosciences have allowed a fundamental understanding of the pathological mechanisms of some epileptic disorders. In the field of human genetics, genes responsible for a number of hereditary epilepsies have been identified and characterized. Significant advances in electrophysiological techniques have led to a deeper understanding of the cellular basis of hyperexcitability and synchronization in individual neurons or groups of neurons. The development of different molecular biological tools now permits to identify and investigate the role of individual candidate molecules important in neuronal dysfunction. Finally, experimental animal models of epilepsy have been developed, which closely resemble the human condition and so are a prerequisite to understand processes of epileptogenesis. A further decisive point, which sets the study of epilepsies apart from other chronic CNS disorders, is the opportunity to obtain living human brain tissue from the seizure focus following resection during epilepsy surgery. Such tissue permits the comparison of molecular and cellular changes in human epilepsy to those occurring in animal models. Significant breakthroughs in the neurosciences together with the unique possibilities associated with the study of human epilepsy, provide the basis for better understanding the pathogenic mechanisms causing epilepsy. Such an understanding is crucial for the development of novel prophylactic strategies and of more effective treatments for epilepsy.
1 Significance of mesial temporal lobe epilepsy (TLE)
Among the different forms of epilepsy, mesial temporal lobe epilepsy (TLE) has a special importance. It is among the most common difficult to treat epileptic syndromes in adults. Surgical removal of mesial temporal lobe tissue is a promissing therapeutic option in many of these patients. In TLE, the epileptic focus is located within a circumscribed area of the mesial temporal lobe, often involving the hippocampus, entorhinal cortex and amygdala. The crucial involvement of these structures in human TLE is supported by several lines of evidence:
- Electroencephalographic recordings – sometimes even with electrodes implanted in brains of TLE patients subjected to presurgical evaluation - frequently show that seizure activity originates in the mesial temporal lobe.
- Focal neuropathological and molecular changes can be observed
within the mesial temporal lobe in brains of TLE patients. One large
group of patients shows a pattern of selective damage in the
hippocampal formation, termed Ammon’s horn sclerosis (AHS). In the
second substantial group of TLE patients, malformative or tumor-like
lesions of mesial temporal structures can be found which in most cases
do not involve the hippocampus itself.
- Surgical removal of the amygdala and of anterior parts of the hippocampus is sufficient to provide seizure relief in most TLE patients with AHS. In the remainder of the cases, the removal of extended portions of the temporal lobe may be necessary for seizure relief.
- TLE is common. Moreover, TLE patients are frequently resistant to anticonvulsant medication, and therefore pose a serious challenge in long-term management.
- The ability to investigate the molecular and cellular basis of TLE is significantly augmented by three major advantages: (i) the availability of many samples of temporal lobe tissue from epilepsy surgery because of the high percentage of resections performed in TLE patients; (ii) the availability of extensively studied animal models of TLE, which bear remarkable similarities in their behavioral, neuropathological and pharmacological manifestations to the human condition; (iii) the well defined anatomy of the structures that give rise to the initiation of seizures, which allows a standardized collection of epileptic tissue for multidisciplinary evaluations.
- Mesial temporal lobe structures involved in TLE are known to have a unique propensity for plastic changes in response to experience-related activity. While this property may be the reason for their frequent involvement in epilepsy, it is considered to be one of the core structures for learning and memory-related processes that take place in the mesial temporal lobe. Thus, the combination of imaging techniques, depth electrode recordings, and neuropsychological testing used to localize and characterize the epileptic focus in human patients can also reveal functional correlates of complex mnestic and emotional processes. Furthermore, studying cellular plasticity induced by seizures and dissecting it from plasticity mechanisms invoked by normal brain activity may shed light on basic mechanisms of learning and memory in the rodent and human brain. Thus, TLE research is not only relevant to unravel dysfunctions of the limbic system, but may also provide us with a window for functions of the normal human brain.
2 The molecular and cellular mechanisms underlying mesial TLE – Research objectives of the consortium I
To fulfill the major goal of this research consortium, we continue to investigate the pathomechanisms of TLE at the molecular and cellular levels. As in the previous funding period, we focus on the following main research objectives:
I.1 Characterization of structural and functional abnormalities
that underlie hyperexcitability in TLE.
I.2 Identification of molecular and cellular mechanisms responsible
for the progression of TLE.
I.3 Clarification of the molecular basis of resistance to
anticonvulsant drugs in TLE.
I.4 Development of novel approaches to suppress epileptic
seizures.
The establishment of a transregional consortium allows us to address these critical issues with a broad arsenal of methods from numerous disciplines including neurosurgery, clinical epilepto-logy, neuropathology, physiology, neurochemistry, human genetics, neuroanatomy, cognitive neuro-science and molecular neurobiology. The collective expertise in these various fields within the SFB has resulted in the development of an integrated strategy to approach some of these critical questions, described in more detail below.
3 Mesial TLE as a model disease to study functional plasticity and cognition in the human brain - Research objectives of the consortium II
Mesial TLE can in many ways be viewed as a model illness in the clinical neurosciences. This paradigmatic nature applies to the following aspects:
II.1 Mesial TLE as a model for plasticity of limbic
structures
II.2 Mechanisms of memory and emotional processes
II.3 Anatomy and function of the human mesial temporal lobe
4 Long-term goals of the research project
The laboratories participating in the proposed long term transregional project will focus on two main areas, the first of which is centered on the investigation of pathomechanisms of mesial TLE (I). A second major topic relates to mechanisms of cognition, memory and emotional processing and their dysfunction in the mesolimbic system (II).
Research objective I.1
Characterization of structural and functional abnormalities that
underlie hyperexcitability in Temporal Lobe Epilepsy
- Changes in synaptic function: Neurotransmitter receptors (B4, B5, C3), neurotransmitter release (C5, B8) and neurotransmitter uptake (C1).
- Changes in intrinsic cellular excitability: Voltage-dependent ion channels (C1, C2, C3, C6, C7)
- Altered properties of glial cells (C1, D6)
- Changes in mitochondrial function and energy production (A7)
Identification of molecular and cellular mechanisms responsible for the progression of TLE
- Altered composition of anticonvulsant drug targets (C7, B5)
- Altered function of multidrug transporters (C7)
Clarification of the molecular basis of resistance to anticonvulsant drugs in TLE
- Mechanisms of neuronal cell death (A7, D9)
- Reorganization of hippocampal connectivity (B4, B5, B8)
- Mechanisms of coordinate gene regulation following seizures (C6)
- Neuronal migration in early development (D6, D7)
Development of novel approaches to suppress epileptic seizures
- Modified surgical procedures (A1, D2)
- Identification of novel pharmacological targets (B4, B5, B8, C1, C2, C3, C5, C6, C7)
- Identification of strategies to halt or slow the chronic progression of epilepsy (C6, D9)
- Transplantation of ES-cell derived neural precursors (D2)
- Seizure prediction (A2)
Mesial TLE as a model for plasticity of limbic structures
- Synaptic long-term plasticity (B8, B9)
- Plasticity of intrinsic excitability (B4, B9, C2, C6, C7)
Mechanisms of memory and emotional processes
- Human memory function (A1, A2, A3)
- Cellular correlates of fear (B7)
Anatomy and function of the human mesial temporal lobe
- Investigation of human amygdala (C3)
- Analysis of the human hippocampus proper (A1, A2, A6, B5, D7)
- Studies on the human subiculum (B4)
5 Advantages of an interdisciplinary consortium for epilepsy research
Despite the fact that epilepsy is one of the most common chronic
neurological disorders and apart from this research consortium research
into this important condition has not been systematically coordinated
between different centers. Other specific research programs or
interdisciplinary networks for epilepsy research do not exist.
This network for investigations on human epileptic brain, in
addition to the availability of excellent models of epilepsy, affords
us with a unique opportunity to address the cellular and molecular
mechanisms of this disorder. An increased understanding of these
mechanisms will further improve our expertise on the function of the
normal brain. These approaches require the use of a wide range of
modern physiological, molecular biological, molecular genetic,
pharmacological and neuroanatomical tools. Furthermore, even in the
case of TLE, it is necessary to focus on multiple subregions and cell
types within the mesial temporal lobe. These technologies are well
beyond the scope of a single research institution, and thus, many
projects can only be carried out when the efforts of several centers
are combined. The four centers in Bonn, Freiburg, Berlin and Magdeburg
and the contributing groups have – amongst other criteria – also been
selected for their contribution to the knowledgebase and expertise
within the SFB. The fact that it was possible to recruit
additional well-qualified junior scientists for the participating
centers demonstrtates the dynamic nature and attraction of our
transregional network.
In addition to these considerations, many projects that involve either
patient material (such as genetic studies or physiological and
molecular studies on resected human tissue) or studies on human
subjects during presurgical evaluation (such as fMRI, MEG and depth
electrode studies on cognitive processes and seizure prediction)
require a sufficient clinical basis. The coordination of protocols
between the four participating centers has resulted in one of the
largest bases for such studies world-wide, and we expect the efficiency
of these collaborations to be further increased in the second funding
period. A Web-based server farm, funded by the DFG and the
participating Universities was established in the first funding period
to facilitate communication and data exchange. The interdisciplinary
network of four centers of clinical epileptology/epilepsy research, all
well embedded in a flourishing neuroscience environment, dispose of
best conditions in order to further improve our understanding of this
important neurological disorder.
6 Scope of the interdisciplinary research consortium: Sections within the transregional SFB
The scientific projects within the SFB are grouped into four major sections (sections A-D), as well as an administrative section (Z). Based on the inclusion of new projects together with the experience gathered in the previous funding period the research goals for these sections have been focused and refined. The four groups of projects cover the following topics:
- Section A: Epilepsy and clinical neurobiology of the limbic system
- Section B: Epilepsy-related plasticity in temporolimbic networks
- Section C: Plasma membrane channels, receptors and transporters as substrates of hyperexcitability and epileptogenesis
- Section D: Neuronal cell death, migration and repair in chronic epilepsy