Epilepsy is a neurological disorder in which normal brain function is disrupted as a consequence of intensive burst activity from groups of neurons. Synchronized population spikes are key concomitants to seizure, but the phenomenon has remained a paradox because it cannot be explained by any known neuronal synaptic mechanism. Several lines of evidence suggest a key role of glutamate in the pathogenesis of depolarization events, which in turn trigger synchronized firing. The observation that astrocytes release glutamate via a regulated Ca2+ dependent mechanism prompted us to hypothesize that glutamate released by astrocytes plays a causal role in epileptogenesis. Our recent study snowed that chemoconvulsive agents including 4-AP and bicuculline triggered TTX-insensitive paroxysmal depolarization shifts in hippocampal slices which were closely correlated with astrocytic Ca2+ oscillations. Photolysis of caged Ca 2+ in astrocytes, but not in neurons, was sufficient to trigger local depolarization events. Furthermore, agents that blocked astrocytic glutamate release reduced epilepiform activity, with no effect on baseline EEC in adult rats. The next critical step is to expand the analysis to reactive astrocytes in epileptic animals. We propose here to analyze astrocytic Ca2+ signaling in epileptic mice with cranial window using 2-photon imaging concomitant with EEC recordings. We will correlate astrocytic signaling in reactive astrocyteswith neuronal firing in epileptic mice. Reactive astrocytes are easily identified in live exposed cortex based upon the intensity of GFP emission in transgenic mice expressing GFP under the GFAP promoter. The hypothesis that the efficacy of antiepileptic drugs is better correlated with the potency by which they reduce astrocytic Ca 2+ signaling and glutamate release, than with their direct effects on synaptic transmission, will be tested. These experiments offer a new conceptual and operational approach to understanding the cellular basis of seizure disorders. If a dysregulation in Ca2+ signaling in reactive astrocytes indeed proves causal in epileptogenesis - asourpreliminary data strongly suggest - then theimplications ofthis newperspective to pharmacotherapy could be profound. By more specifically targeting the glial cause of neuronal excitability, we might be able to achieve more specific, less variable and less toxic treatment options for patients with epilepsy. University of Rochester School of Medicine and Dentistry 601 Elmwood Ave Rochester, NY 14642 PHS 398 (Rev. 04/06) Page 2 Form Page 2 Principal Investigator/Program Director (Last, First, Nedergaard, Maiken Middle): KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator(s). List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Nedergaard, Maiken, MD, DMSc nedergaard University of Rochester PI Tian, Guo-Feng, MD, PhD Guo-Feng_Tian University of Rochester Investigator OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells ^ No D Yes If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://StemcellS.nih.gov/reqistrv/index.asp. Usecontinuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. Cell Line PHS 398 (Rev. 04/06) Page 3 Form Page 2-continued Number the following pages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, First, Middle): Nedergaard, Maiken The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,
| Nedergaard, Maiken; Verkhratsky, Alexei (2012) Artifact versus reality--how astrocytes contribute to synaptic events. Glia 60:1013-23 |
| Oberheim, Nancy Ann; Goldman, Steven A; Nedergaard, Maiken (2012) Heterogeneity of astrocytic form and function. Methods Mol Biol 814:23-45 |
| Huang, Chunlan; Han, Xiaoning; Li, Xi et al. (2012) Critical role of connexin 43 in secondary expansion of traumatic spinal cord injury. J Neurosci 32:3333-8 |
| Kasischke, Karl A; Lambert, Elton M; Panepento, Ben et al. (2011) Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions. J Cereb Blood Flow Metab 31:68-81 |
| Christensen, Daniel J; Nedergaard, Maiken (2011) Two-photon in vivo imaging of cells. Pediatr Nephrol 26:1483-9 |
| Rempe, David A; Nedergaard, Maiken (2010) Targeting glia for treatment of neurological disease. Neurotherapeutics 7:335-7 |
| Hertz, Leif; Lovatt, Ditte; Goldman, Steven A et al. (2010) Adrenoceptors in brain: cellular gene expression and effects on astrocytic metabolism and [Ca(2+)]i. Neurochem Int 57:411-20 |
| Nedergaard, Maiken; Verkhratsky, Alexei (2010) Calcium dyshomeostasis and pathological calcium signalling in neurological diseases. Cell Calcium 47:101-2 |
| Kang, J; Kang, N; Yu, Y et al. (2010) Sulforhodamine 101 induces long-term potentiation of intrinsic excitability and synaptic efficacy in hippocampal CA1 pyramidal neurons. Neuroscience 169:1601-9 |
| Takano, Takahiro; Oberheim, Nancyann; Cotrina, Maria Luisa et al. (2009) Astrocytes and ischemic injury. Stroke 40:S8-12 |
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