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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036692-18
Application #
9459415
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Fountain, Jane W
Project Start
1997-08-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
18
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Miscellaneous
Type
Organized Research Units
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061
Tewari, Bhanu P; Chaunsali, Lata; Campbell, Susan L et al. (2018) Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy. Nat Commun 9:4724
Umans, Robyn A; Sontheimer, Harald (2018) Combating malignant astrocytes: Strategies mitigating tumor invasion. Neurosci Res 126:22-30
Simonds, G R; Marvin, E A; Apfel, L S et al. (2018) Clinical Neuroscience in Practice: An Experiential Learning Course for Undergraduates Offered by Neurosurgeons and Neuroscientists. J Undergrad Neurosci Educ 16:A112-A119
Haring, Alexander P; Sontheimer, Harald; Johnson, Blake N (2017) Microphysiological Human Brain and Neural Systems-on-a-Chip: Potential Alternatives to Small Animal Models and Emerging Platforms for Drug Discovery and Personalized Medicine. Stem Cell Rev 13:381-406
Robel, Stefanie; Sontheimer, Harald (2016) Glia as drivers of abnormal neuronal activity. Nat Neurosci 19:28-33
Thompson, Emily G; Sontheimer, Harald (2016) A role for ion channels in perivascular glioma invasion. Eur Biophys J 45:635-648
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
Kimbrough, Ian F; Robel, Stefanie; Roberson, Erik D et al. (2015) Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. Brain 138:3716-33
Robert, Stephanie M; Buckingham, Susan C; Campbell, Susan L et al. (2015) SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med 7:289ra86
Sontheimer, Harald (2015) Brain cancer: Tumour cells on neighbourhood watch. Nature 528:49-50

Showing the most recent 10 out of 79 publications