The long term goal of this research is to study homeostatic mechanisms that control the excitability of cortical interneurons. Tonically active GABA-A receptors can be a powerful regulator of homeostasis. The overall goal for the research presented in this proposal therefore is the expression and regulation of this inhibitory tonic current (l-Tonic) and these specialized GABA-A receptors. A combination of whole-cell patch-clamp slice electrophysiology, knockout mice, and immunocytochemistry techniques are employed to study tonic inhibition in layer 4 of the mouse somatosensory barrel cortex. There are two primary goals of this proposal. The first goal is to identify cell-type specific basal levels of and mechanisms behind this tonic inhibition. Our preliminary data suggests that two major inhibitory cell types (the regular spiking non pyramidal (RSNP) and the low threshold spiking (LTS)) are inhibited by large tonic currents, mediated at least in part by 6-subunit containing receptors. The second goal is to identify activity- level-dependent, homeostatic, changes in l-Tonic. Whisker plucking alters the level of activity in layer 4 barrel cortex. The second set of experiments proposed here examines the effects of this on excitability and tonic inhibition in cortical neurons. The experiments stemming from this application focus on a basic mechanism that controls the intrinsic plasticity of cortical interneurons and as such is applicable to a broad spectrum of disease states. We use a sensory system that allows us to study use-dependent reductions in cell excitability. Understanding the basic mechanisms that control excitability (e.g., homeostasis) will provide insight for understanding the developmental process of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053719-05
Application #
7804482
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Mamounas, Laura
Project Start
2007-08-15
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$289,882
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
González, Marco I; Grabenstatter, Heidi L; Cea-Del Rio, Christian A et al. (2015) Seizure-related regulation of GABAA receptors in spontaneously epileptic rats. Neurobiol Dis 77:246-56
Li, P; Huntsman, M M (2014) Two functional inhibitory circuits are comprised of a heterogeneous population of fast-spiking cortical interneurons. Neuroscience 265:60-71
Martin, Brandon S; Corbin, Joshua G; Huntsman, Molly M (2014) Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala. J Neurophysiol 112:890-902
Jones, Kevin S; Corbin, Joshua G; Huntsman, Molly M (2014) Neonatal NMDA receptor blockade disrupts spike timing and glutamatergic synapses in fast spiking interneurons in a NMDA receptor hypofunction model of schizophrenia. PLoS One 9:e109303
Vislay, Rebecca L; Martin, Brandon S; Olmos-Serrano, Jose Luis et al. (2013) Homeostatic responses fail to correct defective amygdala inhibitory circuit maturation in fragile X syndrome. J Neurosci 33:7548-58
Martin, Brandon S; Huntsman, Molly M (2012) Pathological plasticity in fragile X syndrome. Neural Plast 2012:275630
Paluszkiewicz, Scott M; Olmos-Serrano, Jose Luis; Corbin, Joshua G et al. (2011) Impaired inhibitory control of cortical synchronization in fragile X syndrome. J Neurophysiol 106:2264-72
Paluszkiewicz, Scott M; Martin, Brandon S; Huntsman, Molly M (2011) Fragile X syndrome: the GABAergic system and circuit dysfunction. Dev Neurosci 33:349-64
Olmos-Serrano, Jose Luis; Paluszkiewicz, Scott M; Martin, Brandon S et al. (2010) Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J Neurosci 30:9929-38
Li, Peijun; Rudolph, Uwe; Huntsman, Molly M (2009) Long-term sensory deprivation selectively rearranges functional inhibitory circuits in mouse barrel cortex. Proc Natl Acad Sci U S A 106:12156-61

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