Cbln1 downregulates the formation and function of inhibitory synapses in mouse cerebellar Purkinje cells

Aya Ishida, Wataru Kakegawa, Kazuhisa Kohda, Eriko Miura, Shigeo Okabe, Michisuke Yuzaki

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The formation of excitatory and inhibitory synapses must be tightly coordinated to establish functional neuronal circuitry during development. In the cerebellum, the formation of excitatory synapses between parallel fibers and Purkinje cells is strongly induced by Cbln1, which is released from parallel fibers and binds to the postsynaptic δ2 glutamate receptor (GluD2). However, Cbln1's role, if any, in inhibitory synapse formation has been unknown. Here, we show that Cbln1 downregulates the formation and function of inhibitory synapses between Purkinje cells and interneurons. Immunohistochemical analyses with an anti-vesicular GABA transporter antibody revealed an increased density of interneuron-Purkinje cell synapses in the cbln1-null cerebellum. Whole-cell patch-clamp recordings from Purkinje cells showed that both the amplitude and frequency of miniature inhibitory postsynaptic currents were increased in cbln1-null cerebellar slices. A 3-h incubation with recombinant Cbln1 reversed the increased amplitude of inhibitory currents in Purkinje cells in acutely prepared cbln1-null slices. Furthermore, an 8-day incubation with recombinant Cbln1 reversed the increased interneuron-Purkinje cell synapse density in cultured cbln1-null slices. In contrast, recombinant Cbln1 did not affect cerebellar slices from mice lacking both Cbln1 and GluD2. Finally, we found that tyrosine phosphorylation was upregulated in the cbln1-null cerebellum, and acute inhibition of Src-family kinases suppressed the increased inhibitory postsynaptic currents in cbln1-null Purkinje cells. These findings indicate that Cbln1-GluD2 signaling inhibits the number and function of inhibitory synapses, and shifts the excitatory-inhibitory balance towards excitation in Purkinje cells. Cbln1's effect on inhibitory synaptic transmission is probably mediated by a tyrosine kinase pathway.

Original languageEnglish
Pages (from-to)1268-1280
Number of pages13
JournalEuropean Journal of Neuroscience
Volume39
Issue number8
DOIs
Publication statusPublished - 2014

Fingerprint

Purkinje Cells
Synapses
Down-Regulation
Interneurons
Cerebellum
Inhibitory Postsynaptic Potentials
Null Lymphocytes
src-Family Kinases
Glutamate Receptors
Synaptic Transmission
Protein-Tyrosine Kinases
Tyrosine
Cell Count
Phosphorylation
Antibodies

Keywords

  • Cerebellum
  • Glutamate receptor
  • Inhibitory synapse
  • Interneuron
  • Purkinje cell

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Cbln1 downregulates the formation and function of inhibitory synapses in mouse cerebellar Purkinje cells. / Ishida, Aya; Kakegawa, Wataru; Kohda, Kazuhisa; Miura, Eriko; Okabe, Shigeo; Yuzaki, Michisuke.

In: European Journal of Neuroscience, Vol. 39, No. 8, 2014, p. 1268-1280.

Research output: Contribution to journalArticle

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