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Cerebellar Nicotinic Cholinergic Receptors are Intrinsic to the Cerebellum: Implications for Diverse Functional Roles

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Abstract

Although recent studies have delineated the specific nicotinic subtypes present in the mammalian cerebellum, very little is known about their location or function within the cerebellum. This is of increased interest since nicotinic receptors (nAChRs) in the cerebellum have recently been implicated in the pathology of autism spectrum disorders. To begin to better understand the roles of these heteromeric nAChRs in the cerebellar circuitry and their therapeutic potential as targets for drug development, we used various chemical and stereotaxic lesion models in conjunction with slice electrophysiology to examine how specific heteromeric nAChR subtypes may influence the surrounding cerebellar circuitry. Using subunit-specific immunoprecipitation of radiolabeled nAChRs in the cerebella following N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, p-chloroamphetamine, and pendunculotomy lesions, we show that most, if not all, cerebellar nicotinic receptors are present in cells within the cerebellum itself and not in extracerebellar afferents. Furthermore, we demonstrate that the β4-containing, but not the β2-containing, nAChRs intrinsic to the cerebellum can regulate inhibitory synaptic efficacy at two major classes of cerebellar neurons. These tandem findings suggest that nAChRs may present a potential drug target for disorders involving the cerebellum.

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Abbreviations

ACh:

Acetylcholine

nAChR:

Nicotinic cholinergic receptor

NE:

Norepinephrine

EB:

Epibatidine

CGC:

Cerebellar granule cell

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Acknowledgments

We thank Dr. Stefano Vicini for helpful discussions about the data presented here. We also thank Drs. Scott Rogers and Lorise Gahring (University of Utah, USA) and Drs. Barry Wolfe and Robert Yasuda (Georgetown University, USA) for providing us with antisera to several nicotinic receptor subunits. This study was supported by NIH grant DA012976 and NIH Training grant NIH-T32-NS41218.

Conflict of Interest

None of the authors have a conflict of interest.

Author information

Author notes

  1. Pavel I. Ortinski

    Present address: Department of Psychiatry, University of Pennsylvania, 125 S. 31st St., Philadelphia, PA, 19106, USA

Authors and Affiliations

  1. Department of Pharmacology, Georgetown University, Washington, DC, 20057, USA

    Jill R. Turner & Kenneth J. Kellar

  2. Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA

    Jill R. Turner, Pavel I. Ortinski & Kenneth J. Kellar

  3. Department of Physiology and Biophysics, Georgetown University, Washington, DC, USA

    Pavel I. Ortinski

  4. Developmental Neuroplasticity Laboratory, School of Anatomy and Human Biology, University of Western Australia, Crawley, Australia

    Rachel M. Sherrard

  5. UMR7102 Neurobiologie des Processus Adaptatifs, UPMC Univ Paris 6, Paris, 75005, France

    Rachel M. Sherrard

Authors
  1. Jill R. Turner
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  2. Pavel I. Ortinski
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  3. Rachel M. Sherrard
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  4. Kenneth J. Kellar
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Corresponding author

Correspondence to Kenneth J. Kellar.

Additional information

Jill R. Turner and Pavel I. Ortinski contributed equally.

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Turner, J.R., Ortinski, P.I., Sherrard, R.M. et al. Cerebellar Nicotinic Cholinergic Receptors are Intrinsic to the Cerebellum: Implications for Diverse Functional Roles. Cerebellum 10, 748–757 (2011). https://doi.org/10.1007/s12311-011-0285-y

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  • DOI: https://doi.org/10.1007/s12311-011-0285-y

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