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TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum

Nature Neuroscience volume 5, pages 225–233 (2002)Cite this article

Abstract

Neurotrophins are essential to the normal development and maintenance of the nervous system. Neurotrophin signaling is mediated by Trk family tyrosine kinases such as TrkA, TrkB and TrkC, as well as by the pan-neurotrophin receptor p75NTR. Here we have deleted the trkB gene in cerebellar precursors by Wnt1-driven Cre–mediated recombination to study the function of the TrkB in the cerebellum. Despite the absence of TrkB, the mature cerebellum of mutant mice appears similar to that of wild type, with all types of cell present in normal numbers and positions. Granule and Purkinje cell dendrites appear normal and the former have typical numbers of excitatory synapses. By contrast, inhibitory interneurons are strongly affected: although present in normal numbers, they express reduced amounts of GABAergic markers and develop reduced numbers of GABAergic boutons and synaptic specializations. Thus, TrkB is essential to the development of GABAergic neurons and regulates synapse formation in addition to its role in the development of axon terminals.

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Figure 1: Wnt1-driven Cre-mediated deletion of the R26R and trkB alleles, identified by expression of the reporters lacZ and tau-lacZ, respectively.
Figure 2: Loss of TrkB receptor in the cerebellum of trkB conditional-mutant mice.
Figure 3: Cerebellar architecture in trkB conditional-mutant mice at P50–P80.
Figure 4: Granular and Purkinje cell morphologies in trkB conditional-mutant mice at P50–P80.
Figure 5: Loss of GABAergic markers in the cerebellum of trkB conditional mutant at P50–P80.
Figure 6: Quantitative analysis of the loss of GABAergic markers in lobule IV and in the fastigial nucleus of trkB conditional-mutant mice at P50–P80.
Figure 7: Reduction in the number of symmetric synapses in the granule-cell layer of trkB conditional-mutant mice at P50–P80.

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Acknowledgements

We thank A. P. McMahon and P. Soriano for the Wnt1Cre and R26R transgenic mice; O. Marín, M. Stryker, S. Bamji, L. Elia, T. Elul, U. Fünfschilling and J. Zhu for comments on the manuscript; S. Huling, and I. Hsie for assistance with electron microscopy; N. Brecha for the antibody against GAT-1; and A. Stephenson for the antibody against the α6 subunit of the GABAA receptor. This work was supported by a grant from the USPH and by the HHMI. B.R. was supported by a postdoctoral fellowship from the Ministerio de Educación, Spain. L.F.R. is an Investigator of the HHMI.

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  1. Howard Hughes Medical Institute and Department of Physiology, University of California, San Francisco, 94143, California, USA

    Beatriz Rico, Baoji Xu & Louis F. Reichardt

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Correspondence to Louis F. Reichardt.

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Rico, B., Xu, B. & Reichardt, L. TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum. Nat Neurosci 5, 225–233 (2002). https://doi.org/10.1038/nn808

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