Many neurons of the cerebellum are spontaneously active, firing 10 to 100 action potentials per second even in the absence of synaptic input. This high basal activity correlates with information coding mechanisms that differ from those of cells in circuits that are generally quiescent until excited synaptically. For example, in the cerebellar nuclei, long-term changes in the strength of excitatory synaptic inputs are not generated by classical Hebbian rules of coincident synaptic excitation and postsynaptic firing. Instead, synaptic currents are potentiated by patterns of stimulation that combine inhibition and excitation, in a manner that resembles the activity of (inhibitory) Purkinje afferents and (excitatory) mossy fiber afferents predicted to occur during cerebellar associative learning tasks. Such results support the idea that cerebellar circuits have rules for information transfer and storage that distinguish them from other well studied brain regions. The present proposal is motivated by the question of how spontaneous firing sets the stage for plasticity that is independent of spike timing. In the proposed research, experiments will be performed on neurons of the cerebellar nuclei in cerebellar slices of mice. Voltage-clamp and current-clamp recordings of synaptic responses, ionic currents, and action potentials, as well as imaging of Ca signals in nuclear cell dendrites, will be directed toward identifying the mechanisms of potentiation of excitatory synaptic responses to mossy fiber input, as well as toward examining the influence of spontaneous activity in Purkinje afferents and nuclear cells on plasticity. The resulting data will provide general information about the fundamental properties of signal encoding across brain regions, as well as specific information about the ionic mechanisms underlying cerebellar synaptic plasticity under normal and pathophysiological conditions.

Public Health Relevance

In the present work, we are studying cells in the cerebellum, a part of the brain that controls the learning and execution of coordinated muscle movements, and whose electrical and chemical signaling patterns are disrupted in ataxia, dystonia, dyslexia, and autism. Because signaling patterns by brain cells depend on specialized proteins called ion channels, we are studying the properties of these ion channels, with the goal of understanding how their activity leads to long-lasting changes in cerebellar signals that are important for motor learning. These data can be used to make comparisons to disrupted signals in the cerebella of animals that have ataxia as a result of genetic mutations of ion channels, with the goal of understanding what goes wrong under pathophysiological conditions and whether ion channels can serve as a target for therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039395-13
Application #
8312596
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Talley, Edmund M
Project Start
1999-12-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
13
Fiscal Year
2012
Total Cost
$323,706
Indirect Cost
$109,331
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
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
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
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
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
Person, Abigail L; Raman, Indira M (2010) Deactivation of L-type Ca current by inhibition controls LTP at excitatory synapses in the cerebellar nuclei. Neuron 66:550-9
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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