Reaktive Astrozyten: Verschiedene Typen, ihre Physiologie und deren Rolle in pathologischen Veränderungen des Gehirns
Zusammenfassung der Projektergebnisse
Astrocytes are responsible for glutamate uptake and recycling of this neurotransmitter und thereby terminating the excitatory signal after neuronal activity within the normal brain. Nervous system damage results in astrocytic changes, known as reactive astrogliosis, in which ion- and neurotransmitter homeostasis can be compromised. Reactive astrogliosis has been reported in epilepsy patients and rodent models of neuronal hyperexcitability, however it is not certain if reactive astrogliosis is causative of seizures or a consequence of changes in the epileptic brain. Just as patients with traumatic brain injury resulting in astrogliosis have a higher incidence of developing epilepsy, up to 70% of patients with primary brain tumors suffer from drugresistant, intractable seizures during the course of the disease. The cellular mechanisms causing tumor-associated epilepsy are largely unknown. High levels of extracellular glutamate have been reported in glioma patients and animal models of glioma, which are likely the cause for seizures in these patients. Interestingly, chronic astrogliosis after conditional deletion of b1-integrins resulted in the development of spontaneous seizures and neuronal hyperexcitabiliy. Important proteins involved in glutamate and potassium homeostasis, such as the glutamate transporters Glt-1 and GLAST, the potassium channel Kir4.1, or glutamine synthetase, were unchanged at the protein level. However, at the functional level, Kir currents and glutamate transporter currents were reduced suggesting that impaired astrocytic functions indeed contribute to seizure generation. In order to address a potential role of astrogliosis in the generation of tumorassociated epilepsy, we took advantage of a mouse model of glioma that presents with an increasing frequency of seizures during the 2-4 weeks course of the disease. Strong astrocyte activation, assessed by immunostaining against glial fibrillary acidic protein, an intermediate filament typically upregulated in reactive astrocytes, and cellular hypertrophy was found in regions surrounding the tumor. Electrophysiological whole cell patch clamp recordings of astrocytes in acute brain slices of tumor-bearing or sham operated animals showed a reduction of potassium currents. Challenging peritumoral astrocytes with high extracellular potassium concentrations confirmed an impairment of astrocytes in potassium uptake. Likewise, pressure applied high extracellular glutamate resulted in transporter currents in control astrocytes, whereas glutamate transport of peritumoral astrocytes was significantly hindered. Taken together, we propose that reactive astrogliosis caused by glioma leads to the breakdown of important homeostatic functions of astrocytes including potassium and glutamate buffering, which contributes to the generation of seizures due to elevated extracellular potassium and glutamate concentrations.
Projektbezogene Publikationen (Auswahl)
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(2011) „Genetic deletion of Cdc42 Reveals a Crucial Role for Astrocyte Recruitment to the Injury Site in vitro and in vivo.” Journal of Neuroscience, Aug 31;31(35):12471-82
Robel S., Bahrdehle S., Lepier A., Brakebusch C., Gotz M.
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(2013) “Glutamate and tumor-associated epilepsy: glial cell dysfunction in the peritumoral environment.” Neurochemistry International, Volume 63, Issue 7, December 2013, Pages 696-701
Buckingham SC. and Robel S.
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“Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells.” Nature Communications volume 5, Article number: 4196 (2014) 15 S.
Watkins S., Robel S., Kimbrough I.F., G. Ellis-Davies, Robert, S.M., and Sontheimer H.
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“GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor‐associated epilepsy.” GLIA Vol 63 Issue 1, January 2015, Pages 23-36. First publ. July 2014
Campbell SL., Robel S., Cuddapah V., Robert S., Buckingham SC., Kahle KT., and Sontheimer H.
