Diseases of cortical malformation cause approximately 25% of all cases of epilepsy. They are also the most common cause for surgical resection of epileptic brain tissue. Almost 80% of people with a cortical malformation suffer from epilepsy and greater than 70% of those people have seizures which are not managed by anti-epileptic drugs. Novel treatment strategies are urgently needed to treat this problematic group of epilepsies. In this proposal we will address the hypothesis that loss of astrocytic glutamate reuptake during the development of a cortical malformation acutely disrupts glutamate homeostasis and has long term effects on synaptic connectivity and cortical network function. Normally, astrocytes remove the neurotransmitter glutamate via glutamate transporters. In diseases of cortical malformation, however, astrocytes become reactive which we believe decreases their ability to remove extracellular glutamate. In the developing cortex glutamate directly drives synapse formation. Therefore, we hypothesize that loss of astrocytic glutamate reuptake during the development of a cortical malformation increases extracellular glutamate levels which promotes excitatory synapse formation and leads to long term cortical hyperexcitability. We will test our hypothesis utilizing cutting-edge imaging techniques, electrophysiological recording from astrocytes, in vivo assays of cortical excitability and molecular disruption and augmentation of astrocyte glutamate transport. Our experiments are extremely innovative. We have developed a novel rodent model of cortical malformation which closely replicates focal cortical dysplasia type 1, a disease with no current animal model. We will utilize exciting, novel glutamate biosensor imaging techniques to assay network function and astrocytic glutamate reuptake. We will record cortical glutamate transporter currents, which have not previously been investigated, and we will do so in the malformed cortex. We will utilize laser-scanning photostimulation to spatially map how astrocytic glutamate reuptake is altered in the malformed cortex. Utilizing molecular modulation of astrocytic glutamate transport we will test whether developmental loss of astrocytic glutamate transport is sufficient to induce cortical hyperexcitability and whether increasing glutamate reuptake in the malformed cortex interrupts epileptogenic processes which we believe lead to later network dysfunction. Importantly, we will utilize drugs which are already clinically available to increase glutamate reuptake. Should this approach successfully attenuate cortical hyperexcitability it could be rapidly translated into a potential anti-epileptogenic clinical tool.

Public Health Relevance

Cortical malformations are a significant cause of epilepsy and are the leading cause of epilepsy requiring resection of brain tissue. Our preliminary studies suggest that astrocytes lose their ability to remove glutamate during the development of cortical malformations. This proposal will test whether these changes contribute to seizures associated with cortical malformation and will test the potential usefulness of clinically available drugs whih target this process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS076885-02
Application #
8496153
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Stewart, Randall R
Project Start
2012-07-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$348,305
Indirect Cost
$137,211
Name
Tufts University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Park, Kellie A; Ribic, Adema; Laage Gaupp, Fabian M et al. (2016) Excitatory Synaptic Drive and Feedforward Inhibition in the Hippocampal CA3 Circuit Are Regulated by SynCAM 1. J Neurosci 36:7464-75
Armbruster, Moritz; Hanson, Elizabeth; Dulla, Chris G (2016) Glutamate Clearance Is Locally Modulated by Presynaptic Neuronal Activity in the Cerebral Cortex. J Neurosci 36:10404-10415
Hanson, Elizabeth; Danbolt, Niels Christian; Dulla, Chris G (2016) Astrocyte membrane properties are altered in a rat model of developmental cortical malformation but single-cell astrocytic glutamate uptake is robust. Neurobiol Dis 89:157-68
Dulla, Chris G; Coulter, Douglas A; Ziburkus, Jokubas (2016) From Molecular Circuit Dysfunction to Disease: Case Studies in Epilepsy, Traumatic Brain Injury, and Alzheimer's Disease. Neuroscientist 22:295-312
Cantu, David; Walker, Kendall; Andresen, Lauren et al. (2015) Traumatic Brain Injury Increases Cortical Glutamate Network Activity by Compromising GABAergic Control. Cereb Cortex 25:2306-20
Hanson, Elizabeth; Armbruster, Moritz; Cantu, David et al. (2015) Astrocytic glutamate uptake is slow and does not limit neuronal NMDA receptor activation in the neonatal neocortex. Glia 63:1784-96
Lillis, Kyle P; Dulla, Chris; Maheshwari, Atul et al. (2015) WONOEP appraisal: molecular and cellular imaging in epilepsy. Epilepsia 56:505-13
Andresen, Lauren; Hampton, David; Taylor-Weiner, Amaro et al. (2014) Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation. Neurobiol Dis 71:305-16
Armbruster, Moritz; Hampton, David; Yang, Yongjie et al. (2014) Laser-scanning astrocyte mapping reveals increased glutamate-responsive domain size and disrupted maturation of glutamate uptake following neonatal cortical freeze-lesion. Front Cell Neurosci 8:277
Tani, Hiroaki; Dulla, Chris G; Farzampour, Zoya et al. (2014) A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. Neuron 81:888-900

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