QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, December 19, 2007, 27(51):14012-14022; doi:10.1523/JNEUROSCI.4390-07.2007

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Pathak, H. R. Articles by Coulter, D. A. Search for Related Content PubMed PubMed Citation Articles by Pathak, H. R. Articles by Coulter, D. A.

 Previous Article  |  Next Article 

Neurobiology of Disease
Disrupted Dentate Granule Cell Chloride Regulation Enhances Synaptic Excitability during Development of Temporal Lobe Epilepsy

Hemal R. Pathak,¹ Florian Weissinger,⁴ Miho Terunuma,¹ Gregory C. Carlson,³ Fu-Chun Hsu,⁴ Stephen J. Moss,¹ and Douglas A. Coulter^1,2,4

Departments of ¹Neuroscience, ²Pediatrics, and ³Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ⁴Pediatric Regional Epilepsy Program and Joseph Stokes Research Institute of the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Douglas A. Coulter, Children's Hospital of Philadelphia, Abramson Pediatric Research Center, Room 410, 3516 Civic Center Boulevard, Philadelphia, PA 19104-4318. Email: coulterd{at}email.chop.edu

GABA_A receptor-mediated inhibition depends on the maintenance of intracellular Cl^– concentration ([Cl^–]_in) at low levels. In neurons in the developing CNS, [Cl^–]_in is elevated, E_GABA is depolarizing, and GABA consequently is excitatory. Depolarizing GABAergic synaptic responses may be recapitulated in various neuropathological conditions, including epilepsy. In the present study, rat hippocampal dentate granule cells were recorded using gramicidin perforated patch techniques at varying times (1–60 d) after an epileptogenic injury, pilocarpine-induced status epilepticus (STEP). In normal, non-epileptic animals, these strongly inhibited dentate granule cells act as a gate, regulating hippocampal excitation, controlling seizure initiation and/or propagation. For 2 weeks after STEP, we found that E_GABA was positively shifted in granule cells. This shift in E_GABA altered synaptic integration, increased granule cell excitability, and resulted in compromised "gate" function of the dentate gyrus. E_GABA recovered to control values at longer latencies post-STEP (2–8 weeks), when animals had developed epilepsy. During this period of shifted E_GABA, expression of the Cl^– extruding K⁺/Cl^– cotransporter, KCC2 was decreased. Application of the KCC2 blocker, furosemide, to control neurons mimicked E_GABA shifts evident in granule cells post-STEP. Furthermore, post-STEP and furosemide effects interacted occlusively, both on E_GABA in granule cells, and on gatekeeper function of the dentate gyrus. This suggests a shared mechanism, reduced KCC2 function. These findings demonstrate that decreased expression of KCC2 persists for weeks after an epileptogenic injury, reducing inhibitory efficacy and enhancing dentate granule cell excitability. This pathophysiological process may constitute a significant mechanism linking injury to the subsequent development of epilepsy.

Key words: temporal lobe epilepsy; dentate gyrus; inhibition; chloride; GABA_A receptor; hippocampus

---

Received April 20, 2007; revised Oct. 25, 2007; accepted Oct. 26, 2007.

Correspondence should be addressed to Dr. Douglas A. Coulter, Children's Hospital of Philadelphia, Abramson Pediatric Research Center, Room 410, 3516 Civic Center Boulevard, Philadelphia, PA 19104-4318. Email: coulterd{at}email.chop.edu

This article has been cited by other articles:

				W. Zhang, R. Yamawaki, X. Wen, J. Uhl, J. Diaz, D. A. Prince, and P. S. Buckmaster Surviving Hilar Somatostatin Interneurons Enlarge, Sprout Axons, and Form New Synapses with Granule Cells in a Mouse Model of Temporal Lobe Epilepsy J. Neurosci., November 11, 2009; 29(45): 14247 - 14256. [Abstract] [Full Text] [PDF]

				H. E. Scharfman, G. H. Malthankar-Phatak, D. Friedman, P. Pearce, D. P. McCloskey, C. L. Harden, and N. J. MacLusky A Rat Model of Epilepsy in Women: A Tool to Study Physiological Interactions between Endocrine Systems and Seizures Endocrinology, September 1, 2009; 150(9): 4437 - 4442. [Abstract] [Full Text] [PDF]

				R.-Z. Zhan and J. V. Nadler Enhanced Tonic GABA Current in Normotopic and Hilar Ectopic Dentate Granule Cells After Pilocarpine-Induced Status Epilepticus J Neurophysiol, August 1, 2009; 102(2): 670 - 681. [Abstract] [Full Text] [PDF]

				E. Delpire, E. Days, L. M. Lewis, D. Mi, K. Kim, C. W. Lindsley, and C. D. Weaver Small-molecule screen identifies inhibitors of the neuronal K-Cl cotransporter KCC2 PNAS, March 31, 2009; 106(13): 5383 - 5388. [Abstract] [Full Text] [PDF]

				A. J. Becker, J. Pitsch, D. Sochivko, T. Opitz, M. Staniek, C.-C. Chen, K. P. Campbell, S. Schoch, Y. Yaari, and H. Beck Transcriptional Upregulation of Cav3.2 Mediates Epileptogenesis in the Pilocarpine Model of Epilepsy J. Neurosci., December 3, 2008; 28(49): 13341 - 13353. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help