Kainate receptors are a functionally unique sub-family of glutamate-gated ion channels that mediate synaptic transmission, modulate neurotransmitter release and regulate cellular excitability in the central nervous system (CNS). Because of the critical role these receptors play in brain function, they have been linked to several neurological conditions including chronic pain, neuroinflammatory demyelinating diseases and temporal lobe epilepsy (TLE). Despite significant progress in recent years, there remain a number of fundamental questions about the function of kainate receptors that have been elusive because comprehensive pharmacological tools targeting the kainate receptors have been lacking. In these studies we will make use of mice with targeted mutations in the genes that encode the kainate receptors in order to address some of these remaining questions. These animal models provide unique opportunities to describe the basic function of these receptors and clarify their contribution to normal and convulsant activity in the brain. Thus, using in vitro electrophysiological recording techniques in brain slices, we will: 1. Delineate the role of calcium permeable kainate receptors in regulating synaptic transmission and developmental plasticity in the hippocampus and cortex;2. Determine the molecular pathways through which kainate receptors modulate intrinsic conductances, and thus regulate neuronal excitability in the hippocampus;3. Test the contribution of postsynaptic kainate receptors to spike coupling, and thus determine their role in the recurrent CA3 network of the hippocampus;a major focus for the generation of synchronized epileptiform activity. These studies will provide important insight into the molecular mechanisms by which kainate receptors affect synapses and cellular excitability, and will validate them as potential therapeutic targets in human (TLE).

Public Health Relevance

Kainate receptors are glutamate-gated neurotransmitter receptors that are critical to synaptic signaling and cellular excitability in the central nervous system. Pathophysiological activation of these receptors has been linked to several important neurological conditions including chronic pain, neuroinflammatory demyelinating diseases, and temporal lobe epilepsy. The goals of this study are to delineate the actions of kainate receptors at synapses and to comprehensively uncover their roles in modulating neuronal excitability, thus providing further validation of these receptors as potential therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058894-04
Application #
8044031
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Whittemore, Vicky R
Project Start
2008-04-01
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
4
Fiscal Year
2011
Total Cost
$295,960
Indirect Cost
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Xu, Jian; Antion, Marcia D; Nomura, Toshihiro et al. (2014) Hippocampal metaplasticity is required for the formation of temporal associative memories. J Neurosci 34:16762-73
Xu, Jian; Zhu, Yongling; Kraniotis, Stephen et al. (2013) Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning. Learn Mem 20:438-45
Catches, Justin S; Xu, Jian; Contractor, Anis (2012) Genetic ablation of the GluK4 kainate receptor subunit causes anxiolytic and antidepressant-like behavior in mice. Behav Brain Res 228:406-14
Contractor, Anis; Mulle, Christophe; Swanson, Geoffrey T (2011) Kainate receptors coming of age: milestones of two decades of research. Trends Neurosci 34:154-63
Xu, J; Cohen, B N; Zhu, Y et al. (2011) Altered activity-rest patterns in mice with a human autosomal-dominant nocturnal frontal lobe epilepsy mutation in the ?2 nicotinic receptor. Mol Psychiatry 16:1048-61
Antion, Marcia D; Christie, Louisa A; Bond, Allison M et al. (2010) Ephrin-B3 regulates glutamate receptor signaling at hippocampal synapses. Mol Cell Neurosci 45:378-88
Harlow, Emily G; Till, Sally M; Russell, Theron A et al. (2010) Critical period plasticity is disrupted in the barrel cortex of FMR1 knockout mice. Neuron 65:385-98
Christie, Louisa A; Russell, Theron A; Xu, Jian et al. (2010) AMPA receptor desensitization mutation results in severe developmental phenotypes and early postnatal lethality. Proc Natl Acad Sci U S A 107:9412-7
Renner, Marianne; Lacor, Pascale N; Velasco, Pauline T et al. (2010) Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron 66:739-54
Fernandes, Herman B; Catches, Justin S; Petralia, Ronald S et al. (2009) High-affinity kainate receptor subunits are necessary for ionotropic but not metabotropic signaling. Neuron 63:818-29

Showing the most recent 10 out of 13 publications