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Selective localization of collybistin at a subset of inhibitory synapses in brain circuits

Authors

  • Annarita Patrizi,

    1. Department of Anatomy, Pharmacology, and Forensic Medicine, National Institute of Neuroscience, I-10126 Torino, Italy
    Current affiliation:
    1. Annarita Patrizi's current address: F.M. Kirby Neurobiology Center, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, CLS 13034, Boston, MA 02115.
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  • Laura Viltono,

    1. Department of Anatomy, Pharmacology, and Forensic Medicine, National Institute of Neuroscience, I-10126 Torino, Italy
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  • Elena Frola,

    1. Department of Anatomy, Pharmacology, and Forensic Medicine, National Institute of Neuroscience, I-10126 Torino, Italy
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  • Kirsten Harvey,

    1. Department of Pharmacology, The School of Pharmacy, London WC1N 1AX, United Kingdom
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  • Robert J. Harvey,

    1. Department of Pharmacology, The School of Pharmacy, London WC1N 1AX, United Kingdom
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  • Marco Sassoè-Pognetto

    Corresponding author
    1. Department of Anatomy, Pharmacology, and Forensic Medicine, National Institute of Neuroscience, I-10126 Torino, Italy
    • Dipartimento di Anatomia, Farmacologia e Medicina Legale, C.so Massimo d'Azeglio, 52, I-10126 Torino, Italy
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Abstract

Collybistin is a brain-specific guanine nucleotide exchange factor (GEF) that is crucial for the postsynaptic accumulation of gephyrin and γ-aminobutyric acid A receptors (GABAARs) at a specific subset of inhibitory synapses. Our understanding of the in vivo function of collybistin has been hampered by lack of information about the synaptic localization of this protein in brain circuits. Here we describe the subcellular localization of endogenous collybistin by using antibodies raised against distinct molecular domains that should recognize the majority of endogenous collybistin isoforms. We show that collybistin co-clusters with gephyrin and GABAARs in synaptic puncta and is recruited to postsynaptic specializations early during synapse development. Notably, collybistin is present in only a subset of gephyrin-positive synapses, with variable co-localization values in different brain regions. Moreover, collybistin co-localizes with GABAARs containing the α1, α2, or α3 subunits, arguing against a selective association with specific GABAAR subtypes. Surprisingly, we found that collybistin is expressed only transiently in Purkinje cells, suggesting that in these cerebellar neurons collybistin plays a selective role during the initial assembly of postsynaptic specializations. These data reveal a remarkable heterogeneity in the organization of GABAergic synapses and provide an anatomical basis for interpreting the variable effects caused by disruption of the collybistin gene in human X-linked intellectual disability and mouse knockout models. J. Comp. Neurol., 2012. © 2011 Wiley Periodicals, Inc.

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