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Characterization of trans-neuronal trafficking of Cbln1.

ABSTRACT: Cbln1, a glycoprotein secreted from granule cells and GluRdelta2 in the postsynaptic densities of Purkinje cells are components of an incompletely understood pathway essential for integrity and plasticity of parallel fiber-Purkinje cell synapses. We show that Cbln1 undergoes anterograde transport from granule cells to Purkinje cells and Bergmann glia, and enters the endolysosomal trafficking system, raising the possibility that Cbln1 exerts its activity on or within Purkinje cells and Bergmann glia. Cbln1 is absent in Purkinje cells and Bergmann glia of GluRdelta2-null mice, suggesting a mechanistic convergence on Cbln1 trafficking. Ectopic expression of Cbln1 in Purkinje cells of L7-cbln1 transgenic mice reveals Cbln1 undergoes anterograde and retrograde trans-neuronal trafficking even across synapses that lack GluRDelta2, indicating that it is not universally essential for Cbln1 transport. The L7-cbln1 transgene also ameliorates the locomotor deficits of cbln1-null mice, indicating that the presence and/or release of Cbln1 from the postsynaptic neuron has functional consequences.

SUBMITTER: Wei P

PROVIDER: S-EPMC2758316 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Characterization of trans-neuronal trafficking of Cbln1.

Wei Peng P Rong Yongqi Y Li Leyi L Bao Dashi D Morgan James I JI

Molecular and cellular neurosciences 20090401 2

Cbln1, a glycoprotein secreted from granule cells and GluRdelta2 in the postsynaptic densities of Purkinje cells are components of an incompletely understood pathway essential for integrity and plasticity of parallel fiber-Purkinje cell synapses. We show that Cbln1 undergoes anterograde transport from granule cells to Purkinje cells and Bergmann glia, and enters the endolysosomal trafficking system, raising the possibility that Cbln1 exerts its activity on or within Purkinje cells and Bergmann g ...[more]

PMID: 19344768

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Project description:The cerebellum is thought to be involved in cognitive functions in addition to its well established role in motor coordination and motor learning in humans. Cerebellin 1 (Cbln1) is predominantly expressed in cerebellar granule cells and plays a crucial role in the formation and function of parallel fiber-Purkinje cell synapses. Although genes encoding Cbln1 and its postsynaptic receptor, the delta2 glutamate receptor (GluD2), are suggested to be associated with autistic-like traits and many psychiatric disorders, whether such cognitive impairments are caused by cerebellar dysfunction remains unclear. In the present study, we investigated whether and how Cbln1 signaling is involved in non-motor functions in adult mice. We show that acquisition and retention/retrieval of cued and contextual fear memory were impaired in Cbln1-null mice. In situ hybridization and immunohistochemical analyses revealed that Cbln1 is expressed in various extracerebellar regions, including the retrosplenial granular cortex and the hippocampus. In the hippocampus, Cbln1 immunoreactivity was present at the molecular layer of the dentate gyrus and the stratum lacunosum-moleculare without overt mRNA expression, suggesting that Cbln1 is provided by perforant path fibers. Retention/retrieval, but not acquisition, of cued and contextual fear memory was impaired in forebrain-predominant Cbln1-null mice. Spatial learning in the radial arm water maze was also abrogated. In contrast, acquisition of fear memory was affected in cerebellum-predominant Cbln1-null mice. These results indicate that Cbln1 in the forebrain and cerebellum mediates specific aspects of fear conditioning and spatial memory differentially and that Cbln1 signaling likely regulates motor and non-motor functions in multiple brain regions. SIGNIFICANCE STATEMENT:Despites its well known role in motor coordination and motor learning, whether and how the cerebellum is involved in cognitive functions remains less clear. Cerebellin 1 (Cbln1) is highly expressed in the cerebellum and serves as an essential synaptic organizer. Although genes encoding Cbln1 and its receptor are associated with many psychiatric disorders, it remains unknown whether such cognitive impairments are caused by cerebellar dysfunction. Here, we show that Cbln1 is also expressed in the forebrain, including the hippocampus and retrosplenial granular cortex. Using forebrain- and cerebellum-predominant conditional Cbln1-null mice, we show that Cbln1 in the forebrain and cerebellum mediates specific aspects of fear conditioning and spatial memory differentially, indicating that Cbln1 signaling regulates both motor and non-motor functions in multiple brain regions.

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Characterization of trans-neuronal trafficking of Cbln1.

Publications

Characterization of trans-neuronal trafficking of Cbln1.

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