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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Talley, Edmund M
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Northwestern University at Chicago
Schools of Arts and Sciences
United States
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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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