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Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing.
J Neurosci. 2015 Aug 12; 35(32):11433-44.JN

Abstract

A specialized axonal ending, the basket cell "pinceau," encapsulates the Purkinje cell axon initial segment (AIS), exerting final inhibitory control over the integrated outflow of the cerebellar cortex. This nonconventional axo-axonic contact extends beyond the perisomatic chemical GABAergic synaptic boutons to the distal AIS, lacks both sodium channels and local exocytotic machinery, and yet contains a dense cluster of voltage-gated potassium channels whose functional contribution is unknown. Here, we show that ADAM11, a transmembrane noncatalytic disintegrin, is the first reported Kv1-interacting protein essential for localizing Kv1.1 and Kv1.2 subunit complexes to the distal terminal. Selective absence of these channels at the pinceau due to mutation of ADAM11 spares spontaneous GABA release from basket cells at the perisomatic synapse yet eliminates ultrarapid ephaptic inhibitory synchronization of Purkinje cell firing. Our findings identify a critical role for presynaptic K(+) channels at the pinceau in ephaptic control over the speed and stability of spike rate coding at the Purkinje cell AIS in mice.

SIGNIFICANCE STATEMENT

This study identifies ADAM11 as the first essential molecule for the proper localization of potassium ion channels at presynaptic nerve terminals, where they modulate excitability and the release of neural transmitters. Genetic truncation of the transmembrane disintegrin and metalloproteinase protein ADAM11 resulted in the absence of Kv1 channels that are normally densely clustered at the terminals of basket cell axons in the cerebellar cortex. These specialized terminals are responsible for the release of the neurotransmitter GABA onto Purkinje cells and also display electrical signaling. In the ADAM11 mutant, GABAergic release was not altered, but the ultrarapid electrical signal was absent, demonstrating that the dense presynaptic cluster of Kv1 ion channels at these terminals mediate electrical transmission. Therefore, ADAM11 plays a critical role at this central synapse.

Authors+Show Affiliations

Developmental Neurogenetics Laboratory, Department of Neurology.Developmental Neurogenetics Laboratory, Department of Neurology.Laboratory of Biochemical Genetics, Rockefeller University, New York, New York 10065, and.Developmental Neurogenetics Laboratory, Department of Neurology.Developmental Neurogenetics Laboratory, Department of Neurology.Institute of Molecular and Cell Biology, Singapore 138673.Developmental Neurogenetics Laboratory, Department of Neurology, Department of Neuroscience, and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, jnoebels@bcm.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26269648

Citation

Kole, Matthew J., et al. "Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 35, no. 32, 2015, pp. 11433-44.
Kole MJ, Qian J, Waase MP, et al. Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing. J Neurosci. 2015;35(32):11433-44.
Kole, M. J., Qian, J., Waase, M. P., Klassen, T. L., Chen, T. T., Augustine, G. J., & Noebels, J. L. (2015). Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 35(32), 11433-44. https://doi.org/10.1523/JNEUROSCI.1346-15.2015
Kole MJ, et al. Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing. J Neurosci. 2015 Aug 12;35(32):11433-44. PubMed PMID: 26269648.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing. AU - Kole,Matthew J, AU - Qian,Jing, AU - Waase,Marc P, AU - Klassen,Tara L, AU - Chen,Tim T, AU - Augustine,George J, AU - Noebels,Jeffrey L, PY - 2015/8/14/entrez PY - 2015/8/14/pubmed PY - 2015/11/6/medline KW - Kv1.1 KW - ataxia KW - disintegrin KW - epilepsy KW - presynaptic terminal KW - synchrony SP - 11433 EP - 44 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 35 IS - 32 N2 - UNLABELLED: A specialized axonal ending, the basket cell "pinceau," encapsulates the Purkinje cell axon initial segment (AIS), exerting final inhibitory control over the integrated outflow of the cerebellar cortex. This nonconventional axo-axonic contact extends beyond the perisomatic chemical GABAergic synaptic boutons to the distal AIS, lacks both sodium channels and local exocytotic machinery, and yet contains a dense cluster of voltage-gated potassium channels whose functional contribution is unknown. Here, we show that ADAM11, a transmembrane noncatalytic disintegrin, is the first reported Kv1-interacting protein essential for localizing Kv1.1 and Kv1.2 subunit complexes to the distal terminal. Selective absence of these channels at the pinceau due to mutation of ADAM11 spares spontaneous GABA release from basket cells at the perisomatic synapse yet eliminates ultrarapid ephaptic inhibitory synchronization of Purkinje cell firing. Our findings identify a critical role for presynaptic K(+) channels at the pinceau in ephaptic control over the speed and stability of spike rate coding at the Purkinje cell AIS in mice. SIGNIFICANCE STATEMENT: This study identifies ADAM11 as the first essential molecule for the proper localization of potassium ion channels at presynaptic nerve terminals, where they modulate excitability and the release of neural transmitters. Genetic truncation of the transmembrane disintegrin and metalloproteinase protein ADAM11 resulted in the absence of Kv1 channels that are normally densely clustered at the terminals of basket cell axons in the cerebellar cortex. These specialized terminals are responsible for the release of the neurotransmitter GABA onto Purkinje cells and also display electrical signaling. In the ADAM11 mutant, GABAergic release was not altered, but the ultrarapid electrical signal was absent, demonstrating that the dense presynaptic cluster of Kv1 ion channels at these terminals mediate electrical transmission. Therefore, ADAM11 plays a critical role at this central synapse. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/26269648/Selective_Loss_of_Presynaptic_Potassium_Channel_Clusters_at_the_Cerebellar_Basket_Cell_Terminal_Pinceau_in_Adam11_Mutants_Reveals_Their_Role_in_Ephaptic_Control_of_Purkinje_Cell_Firing_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=26269648 DB - PRIME DP - Unbound Medicine ER -