Comparison of Cbln1 and Cbln2 functions using transgenic and knockout mice

Abstract

Cbln1 is the prototype of a family of secreted neuronal glycoproteins (Cbln1-4) and its genetic elimination results in synaptic alterations in cerebellum and striatum. In cerebellum, Cbln1 acts as a bi-functional ligand bridging pre-synaptic β-neurexins on granule cells to post-synaptic Grid2 on Purkinje neurons. Although much is known concerning the action of Cbln1, little is known of the function of its other family members. Here we show that Cbln1 and Cbln2 have similar binding activities to β-neurexins and Grid2 and the targeted ectopic expression of Cbln2 to Purkinje cells in transgenic mice rescues the cerebellar deficits in Cbln1-null animals: suggesting the two proteins have redundant function mediated by their common receptor binding properties. Cbln1 and Cbln2 are also co-expressed in the endolysosomal compartment of the thalamic neurons responsible for the synaptic alterations in striatum of Cbln1-null mice. Therefore, to determine whether the two family members have similar functions we generated Cbln2-null mice. Cbln2-null mice do not show the synaptic alterations evident in striatum of Cbln1-null mice. Thus Cbln2 can exhibit functional redundancy with Cbln1 in cerebellum but it does not have the same properties as Cbln1 in thalamic neurons, implying one or both utilize different receptors/mechanisms in this brain region.

Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism

“…97, 98 This is of particular relevance given the common association of TS with ADHD and OCD and that the GRID1 knockout mouse presents with hyperactivity and aberrant emotional and social behaviours, 98 which contrasts markedly with the ataxic presentation of the GRID2 knockout mouse. 99 The behavioural phenotype of the CBLN2 knockout mouse 100 is eagerly anticipated. At the molecular level GRID1's preferential role with CBLN2 in the induction of inhibitory presynaptic differentiation 101 suggests that reduced inhibitory synaptogenesis may represent a distinguishing molecular feature of TS compared with ASD but this remains to be tested.…”

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

“…Cbln1, Cbln2, and Cbln4 KO mice are viable; thus, individual cerebellins are not essential for survival (Hirai et al, 2005; Rong et al, 2012; Wei et al, 2012; Haddick et al, 2014). 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).…”

“…In cerebellum – the only brain region extensively analyzed - Cbln1 and GluD2 KO mice exhibit a decrease in parallel-fiber synapses formed by granule cells on Purkinje cell spines, with a loss of presynaptic terminals and the appearance of ‘naked spines’ (Kashiwabuchi et al, 1995; Hirai et al, 2005; Rong et al, 2012). Importantly, the loss of parallel-fiber synapses is only partial (~30–50% depending on the study) and primarily found on distal dendrites of Purkinje cells, and is not associated with a decrease in spine density (hence the ‘naked spines’; Hirai et al, 2005).…”

GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia

“…12,13 The GluRD2 general structure is similar to other iGluRs, with an extracellular ligand binding domain composed of 2 segments (S1 and S2), 4 transmembrane segments (M1-M4) of which M1, M3, and M4 are responsible for the channel pore formation, and 3 linkers (S1M1, M3S2, S2M4). 15 Recently, it was proven, in vitro and in mice, that GluRD2 and cerebellin-1 form a complex acting as a synapse organizer between PFs and PCs 16,17 and that GluRD2 also has a major role in long-term depression at this synapse, 13,[18][19][20] possibly through the regulation of AMPA receptors endocytosis. 15 Recently, it was proven, in vitro and in mice, that GluRD2 and cerebellin-1 form a complex acting as a synapse organizer between PFs and PCs 16,17 and that GluRD2 also has a major role in long-term depression at this synapse, 13,[18][19][20] possibly through the regulation of AMPA receptors endocytosis.…”