Many neurons are silent until excited synaptically. In some circuits, including those of the cerebellum, however, it is becoming clear that individual neurons are intrinsically active, firing regular action potentials spontaneously, in the absence of synaptic input. In such neurons, rather than inducing or preventing action potentials, synaptic excitation or inhibition modulates the intrinsic firing pattern. The current proposal is motivated by the question of what constitutes signal and what constitutes noise in a system with spontaneously active elements. The goal is to explore the mechanisms underlying """"""""effective"""""""" synaptic signals--i.e. , those that significantly modify postsynaptic firing--and ultimately to test the consequences of modulating or disrupting synaptic signals, either by plasticity or by pathophysiology. The proposed research focuses on synaptic transmission between Purkinje neurons and cerebellar nuclear neurons. Tissue will be used from 2-3 week old wild-type and ataxic mice. Experiments will be performed on cerebellar nuclear neurons either in acute isolation or in cerebellar slices in which synaptic contacts from Purkinje neurons are intact. Voltage-clamp and current-clamp recordings of inhibitory synaptic responses evoked by stimulation of Purkinje cell afferents, recordings of inhibitory neurotransmitter receptor kinetics, and histological studies will be used to examine the mechanisms underlying synaptic depression at the Purkinje-to-nuclear cell synapse. The resulting data will provide general information about the adaptive significance of spontaneously active elements in neural circuits, as well as specific information about cellular basis of information transfer in the functional and dysfunctional cerebellum. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS039395-05
Application #
6731386
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Talley, Edmund M
Project Start
1999-12-01
Project End
2008-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
5
Fiscal Year
2004
Total Cost
$301,664
Indirect Cost
Name
Northwestern University at Chicago
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Najac, Marion; Raman, Indira M (2015) Integration of Purkinje cell inhibition by cerebellar nucleo-olivary neurons. J Neurosci 35:544-9
Lewis, Amanda H; Raman, Indira M (2014) Resurgent current of voltage-gated Na(+) channels. J Physiol 592:4825-38
Benton, Mark D; Lewis, Amanda H; Bant, Jason S et al. (2013) Iberiotoxin-sensitive and -insensitive BK currents in Purkinje neuron somata. J Neurophysiol 109:2528-41
Lewis, Amanda H; Raman, Indira M (2013) Interactions among DIV voltage-sensor movement, fast inactivation, and resurgent Na current induced by the NaV?4 open-channel blocking peptide. J Gen Physiol 142:191-206
Bant, Jason S; Aman, Teresa K; Raman, Indira M (2013) Antagonism of lidocaine inhibition by open-channel blockers that generate resurgent Na current. J Neurosci 33:4976-87
Person, Abigail L; Raman, Indira M (2012) Purkinje neuron synchrony elicits time-locked spiking in the cerebellar nuclei. Nature 481:502-5
Zheng, Nan; Raman, Indira M (2011) Prolonged postinhibitory rebound firing in the cerebellar nuclei mediated by group I metabotropic glutamate receptor potentiation of L-type calcium currents. J Neurosci 31:10283-92
Lewis, Amanda H; Raman, Indira M (2011) Cross-species conservation of open-channel block by Na channel ?4 peptides reveals structural features required for resurgent Na current. J Neurosci 31:11527-36
Bant, Jason S; Raman, Indira M (2010) Control of transient, resurgent, and persistent current by open-channel block by Na channel beta4 in cultured cerebellar granule neurons. Proc Natl Acad Sci U S A 107:12357-62
Aman, Teresa K; Raman, Indira M (2010) Inwardly permeating Na ions generate the voltage dependence of resurgent Na current in cerebellar Purkinje neurons. J Neurosci 30:5629-34

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