Role of Cl- channels and transporters in tumor-associated epilepsy Abstract: Primary brain tumors, gliomas, release copious amounts of glutamate (Glu) into the extracellular space, inflicting excitotoxic injury that facilitates tumor expansion. Neurons in the tumors vicinity are hyperexcitable, and many patients develop tumor-associated epilepsy that can be unresponsive to traditional anti-epileptic medications. While enhanced Glu release from the tumor and/or impaired Glu clearance from the extracellular space are well documented, and appear to be necessary to induce peritumoral seizures, the mechanism(s) whereby this induces sustained hyperexcitability are not well understood. This proposal posits as a central hypothesis that glioma-released Glu causes seizures by impairing neuronal inhibition. We put forth three specific hypotheses that each mechanistically link glioma-released Glu to impaired inhibition and hence the development of tumor-associated epilepsy, namely: (1) A loss of excitatory amino acid transporters (EAATs) in tumor-associated astrocytes which presents with two consequences: First, it results in a build-up of extracellular Glu sufficient to causes excitotoxic death to GABAergic neurons;second, astrocytes no longer convert Glu to glutamine required as a substrate for the neuronal synthesis of GABA. The resulting loss of neuronal GABA and/or GABAergic neurons enhances excitability. (2) Conversion of GABA to become an excitatory transmitter. Tumor-released Glu activates neuronal NMDA-R causing enhanced postsynaptic Ca2+ influx. This activates two kinases (PKC and WNK3) causing the differential phosphorylation of KCC2 at T906 and S940, resulting in a loss of KCC function. The resulting increase in intracellular [Cl-] converts the action of GABA from inhibitory to excitatory. (3) NMDA-R-mediated Ca2+ influx into postsynaptic terminals recruits Ca2+- activated Cl- channels, which potentiate postsynaptic excitatory response when intracellular [Cl-] is elevated. Each of the hypothesized mechanisms can operate singly or in combination. Importantly each pathway can be disrupted by pharmacologically targeting known proteins, and therefore this research has the potential to uncover a number of new therapeutic targets to disrupt peritumoral epilepsy and tumor growth.

Public Health Relevance

Many brain tumor patients suffer from intractable seizures. This project studies the novel hypothesis that tumor-associated epilepsy is due to a loss of normal GABA function concomitant with enhanced glutamate release from the tumor. A clinically relevant mouse model of disease, which replicates the salient features of the disease, will be used for this multi-modal study.

National Institute of Health (NIH)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Fountain, Jane W
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University of Alabama Birmingham
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Campbell, Susan L; Robel, Stefanie; Cuddapah, Vishnu A et al. (2015) GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy. Glia 63:23-36
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Turner, Kathryn L; Sontheimer, Harald (2014) KCa3.1 modulates neuroblast migration along the rostral migratory stream (RMS) in vivo. Cereb Cortex 24:2388-400
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