Cbln1 downregulates the formation and function of inhibitory synapses in mouse cerebellar Purkinje cells. (27th January 2014)

• Record Type: Journal Article
• Authors: Ito‐Ishida, Aya; Kakegawa, Wataru; Kohda, Kazuhisa; Miura, Eriko; Okabe, Shigeo; Yuzaki, Michisuke
• Is Part Of: European journal of neuroscience. Volume 39:Number 8(2014:Apr.)
• Page Start: 1268
• Page End: 1280
• Publication Date: 2014-01-27
• Subjects: Nervous system -- Periodicals; 612.8
• DOI: 10.1111/ejn.12487
• Languages: English
• ISSNs: 0953-816X

Abstract

<abstract abstract-type="main" id="ejn12487-abs-0001"> <title>Abstract</title> <p>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 <italic>cbln1</italic>‐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 <italic>cbln1</italic>‐null cerebellar slices. A 3‐h incubation with recombinant Cbln1 reversed the increased amplitude of inhibitory currents in Purkinje cells in acutely prepared <italic>cbln1</italic>‐null slices. Furthermore, an 8‐day incubation with recombinant Cbln1 reversed the increased interneuron–Purkinje cell synapse density in cultured <italic>cbln1</italic>‐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 <italic>cbln1</italic>‐null cerebellum, and acute inhibition of Src‐family kinases suppressed the increased inhibitory postsynaptic currents in <italic>cbln1</italic>‐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.</p> </abstract>