Febrile (fever-induced) seizures are the most common forms of childhood seizures, affecting 3%-5% of infants and young children in the United States and worldwide. In spite of the high incidence of fever-induced seizures, whether and how febrile seizures in the developing brain alter neuronal circuits is not well understood. Under the previous award, using an appropriate-aged rodent model of febrile seizures, we determined that experimental febrile seizures in infant rats resulted in a persistent increase in the number of cannabinoid receptor type 1- (CB1-) receptors, and an enhancement of the CB1-mediated, activity- dependent, retrograde suppression of the release of the neurotransmitter GABA in the hippocampus. Here we propose to test the hypotheses that 1. febrile seizures selectively alter the intrinsic, synaptic and electrical coupling properties of the CB1-expressing basket cells, without modifying other types of perisomatically projecting interneurons; 2. febrile seizures persistently increase the CB1 receptor-mediated tonic inhibition of GABA-release from basket cell terminals; and that 3. CB1 receptor activation during the experimental febrile seizures in infancy is a key step in causing long-lasting changes in limbic network excitability. These hypotheses will be tested using a combination of electrophysiological methods and immunocytochemical techniques, complemented by large-scale, anatomically and biophysically realistic, computational network modeling approaches that allow the systematic testing of the relative importance of the various, experimentally determined, seizure-induced alterations in hyperexcitability. Two types of controls will be employed: 1) age-matched, normothermic sham controls, and 2) age-matched, hyperthermic controls, in which the seizures are blocked using pharmacological agents. Our Preliminary data indicate that long-term alterations in CB1 receptors, which are the most abundant G-protein-coupled receptors in the mammalian brain, play crucial mechanistic roles in the development and maintenance of increased limbic excitability after experimental febrile seizures. The experiments in this proposal are designed to specifically target major cellular-synaptic mechanisms underlying hyperexcitability following febrile seizures in infancy and it is anticipated that the proposed experiments may provide novel future therapeutic avenues for anti-epileptic drug therapies in children. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS038580-08
Application #
7088401
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Jacobs, Margaret
Project Start
1999-04-15
Project End
2011-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
8
Fiscal Year
2006
Total Cost
$297,305
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Winterer, Jochen; Stempel, A Vanessa; Dugladze, Tamar et al. (2011) Cell-type-specific modulation of feedback inhibition by serotonin in the hippocampus. J Neurosci 31:8464-75
Lee, Sang-Hun; Soltesz, Ivan (2011) Requirement for CB1 but not GABAB receptors in the cholecystokinin mediated inhibition of GABA release from cholecystokinin expressing basket cells. J Physiol 589:891-902
Lee, Soo Yeun; Soltesz, Ivan (2011) Cholecystokinin: a multi-functional molecular switch of neuronal circuits. Dev Neurobiol 71:83-91
Lee, Soo Yeun; Foldy, Csaba; Szabadics, Janos et al. (2011) Cell-type-specific CCK2 receptor signaling underlies the cholecystokinin-mediated selective excitation of hippocampal parvalbumin-positive fast-spiking basket cells. J Neurosci 31:10993-1002
Lee, Sang-Hun; Foldy, Csaba; Soltesz, Ivan (2010) Distinct endocannabinoid control of GABA release at perisomatic and dendritic synapses in the hippocampus. J Neurosci 30:7993-8000
Foldy, Csaba; Lee, Sang-Hun; Morgan, Robert J et al. (2010) Regulation of fast-spiking basket cell synapses by the chloride channel ClC-2. Nat Neurosci 13:1047-9
Armstrong, Caren; Morgan, Robert J; Soltesz, Ivan (2009) Pursuing paradoxical proconvulsant prophylaxis for epileptogenesis. Epilepsia 50:1657-69
Foldy, Csaba; Lee, Soo Yeun; Szabadics, Janos et al. (2007) Cell type-specific gating of perisomatic inhibition by cholecystokinin. Nat Neurosci 10:1128-30
Neu, Axel; Foldy, Csaba; Soltesz, Ivan (2007) Postsynaptic origin of CB1-dependent tonic inhibition of GABA release at cholecystokinin-positive basket cell to pyramidal cell synapses in the CA1 region of the rat hippocampus. J Physiol 578:233-47
Chen, Kang; Neu, Axel; Howard, Allyson L et al. (2007) Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures. J Neurosci 27:46-58

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