Epilepsy-induced plasticity

Mesial temporal lobe epilepsy (TLE) is the most prevalent form of focal epilepsies. It is associated with severe neurodegenerative changes in the hippocampal formation. Up to 50 % of the TLE patients are resistant to pharmacotherapy. These patients have the option for a neurosurgical removal of the epileptic focus and then become often seizure-free or responsive to drug therapy. In rat models of TLE, initially a status epilepticus is induced; this is followed by a latent period in which epilepsy develops, characterized by the occurrence of spontaneous limbic seizures. Both in animal models of TLE and in tissue from TLE patients, numerous morphological and neurochemical changes were observed in the hippocampus and related brain areas. These changes are part of the TLE-induced plasticity contributing either to the development of epilepsy or to self- protective mechanisms, and may also take part in developing drug-resistance. Our project will address two major issues related to the pathomechanisms in epilepsy and epileptogenesis: 1) We will investigate at the pre- and postsynaptic level changes in the GABA-ergic system in tissue obtained at surgery from patients with drug-refractory TLE, and 2) we will conduct a detailed histochemical analysis of the subiculum and parahippocampal areas in an animal model of TLE and in the epileptic human hippocampus. In particular, we will investigate whether glutamate decarboxylases (GAD67 and GAD65) are expressed in mossy fibers, an important glutamatergic pathway. We have demonstrated this in previous studies in rat models of TLE. The implication of such a finding would be that also in humans the excitatory mossy fibers may contribute to inhibitory mechanisms in TLE. Furthermore, we will extend our studies on the expression of GABA A receptor subunits in the epileptic human hippocampus. We will focus on subunits (notably subunits a2, a4, a5 and d) not investigated by us before. The hypothesis of this study is that the subunit composition of GABA A receptors is altered in certain neurons in TLE. Such changes may reflect changes in inhibitory neurotransmission and may contribute to the drug resistance of the patients. In the second part of the project (closely related to the first one), we will conduct a detailed histochemical analysis of the subiculum and of parahippocampal areas in a rat model of TLE and in human TLE tissue. We will use histochemical methods (immunohistochemistry, in situ hybridization, receptor autoradiography, tracer studies) aiming to identify sprouting and neurochemical plasticity in these brain areas. The subiculum is the major hippocampal output region. Whereas most parts of the hippocampus are highly damaged in TLE, the subiculum remains almost entirely preserved. Our hypothesis is that the subiculum may undergo considerable plastic changes in TLE and that these changes may importantly contribute to the generation of epileptic activity arising from the hippocampal formation in TLE.

Mesial temporal lobe epilepsy (TLE) is the most prevalent form of focal epilepsies. It is associated with severe neurodegenerative changes in the hippocampal formation. Up to 50 % of the TLE patients are resistant to pharmacotherapy. These patients have the option for a neurosurgical removal of the epileptic focus and then become often seizure-free or responsive to drug therapy. In rat models of TLE, initially a status epilepticus is induced; this is followed by a latent period in which epilepsy develops, characterized by the occurrence of spontaneous limbic seizures. Both in animal models of TLE and in tissue from TLE patients, numerous morphological and neurochemical changes were observed in the hippocampus and related brain areas. These changes are part of the TLE-induced plasticity contributing either to the development of epilepsy or to self- protective mechanisms, and may also take part in developing drug-resistance. Our project will address two major issues related to the pathomechanisms in epilepsy and epileptogenesis: 1) We will investigate at the pre- and postsynaptic level changes in the GABA-ergic system in tissue obtained at surgery from patients with drug-refractory TLE, and 2) we will conduct a detailed histochemical analysis of the subiculum and parahippocampal areas in an animal model of TLE and in the epileptic human hippocampus. In particular, we will investigate whether glutamate decarboxylases (GAD67 and GAD65) are expressed in mossy fibers, an important glutamatergic pathway. We have demonstrated this in previous studies in rat models of TLE. The implication of such a finding would be that also in humans the excitatory mossy fibers may contribute to inhibitory mechanisms in TLE. Furthermore, we will extend our studies on the expression of GABA A receptor subunits in the epileptic human hippocampus. We will focus on subunits (notably subunits a2, a4, a5 and d) not investigated by us before. The hypothesis of this study is that the subunit composition of GABA A receptors is altered in certain neurons in TLE. Such changes may reflect changes in inhibitory neurotransmission and may contribute to the drug resistance of the patients. In the second part of the project (closely related to the first one), we will conduct a detailed histochemical analysis of the subiculum and of parahippocampal areas in a rat model of TLE and in human TLE tissue. We will use histochemical methods (immunohistochemistry, in situ hybridization, receptor autoradiography, tracer studies) aiming to identify sprouting and neurochemical plasticity in these brain areas. The subiculum is the major hippocampal output region. Whereas most parts of the hippocampus are highly damaged in TLE, the subiculum remains almost entirely preserved. Our hypothesis is that the subiculum may undergo considerable plastic changes in TLE and that these changes may importantly contribute to the generation of epileptic activity arising from the hippocampal formation in TLE.