Roles of Cbln1 in Non-Motor Functions of Mice

Abstract

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.

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

“…Only Cbln1 KO mice have been analyzed in detail, and exhibit a phenotype that is virtually identical to that of GluD2 KO mice (Hirai et al, 2005; Otsuka et al, 2016; Kusnoor et al, 2010; Ito-Ishida et al, 2008 and 2014). The fact that Nrxn1 and Nrxn3 are essential for survival (Missler et al, 2003; Aoto et al, 2015), but their binding partners cerebellins and GluD2 are not, may be due to the interactions of neurexins with many different postsynaptic partners, whereas Cbln1 and Cbln2 and GluD2 appear to only bind to each other and to neurexins, and thus only mediate part of the overall functions of neurexins.…”

“…The loss of Cbln1 signaling may cause distinct downstream, region-dependent effects on synapse stability, accounting for the different phenotypes of Cbln1-deficient cerebellum and striatum. Moreover, Cbln1 was shown to be essential for hippocampal learning by an unknown mechanism, even though cerebellins are not expressed in the hippocampus proper (Otsuka et al, 2016). Thus, our understanding of Cbln1 function is incomplete, and even less is known about the functions of Cbln2 and Cbln4.…”

Cerebellins are differentially expressed in selective subsets of neurons throughout the brain

“…Here, Cbln1‐deficient thalamic axons exhibited an increase in synaptic spine density instead of a synapse loss, suggesting that cerebellins may in general perform a signaling function instead of a synapse‐formation function. Moreover, Cbln1 was shown to be essential for hippocampal learning by an unknown mechanism (Otsuka et al, ). Although our understanding of Cbln1 function is thus incomplete, even less is known about the expression patterns and functions of Cbln2 and Cbln4.…”

Single cell analyses of the effects of Amyloid-beta42 and Interleukin-4 on neural stem/progenitor cell plasticity in adult zebrafish brain

“…Two out of the remaining five neuronal clusters can be classified as GABAergic interneurons (GIs, neurod6a+ and gabrb3+ ) (Butt et al, 2007; Lujan et al, 2005; Ohtsuka et al, 2011) and based on Parvalbumin expression can be separated into pvalb7a+ GIs (GIs+) and pvalb7a− GIs (GIs−) (Figure 2; Dataset S1B). The remaining three clusters are comprised of commissural neurons (CN, cbln1+ and eomesa+ ) (Cameron et al, 2012; Otsuka et al, 2016), corticospinal projection/Cajal-Retzius neurons (CPN, lhx5+ and tbr1b+ ) (Bedogni et al, 2010; Miquelajauregui et al, 2010) and motor neuron progenitors/excitatory neuron progenitors (MNP, eomesa+ and ets2+ ) (Cameron et al, 2012; Lake et al, 2016). We could also verify the initial clustering of cell types with further markers such as endothelium ( cd9b , aplnrb ) (Klein-Soyer et al, 2000; Reaux et al, 2001), neuroepithelium ( krt18 , tagln2 ) (Lee et al, 2014; Merrick et al, 1995; Pollen et al, 2015) and mixed immune cells ( pfn1 and cd74 ) (Fan et al, 2014; Gil-Yarom et al, 2017).…”