Increasing UBE3A in the nucleus and epileptic seizures were both shown to repress Cbln1 levels in Krishnan et al., 2017; deletion of Cbln1 in glutamate neurons of the midbrain ventral tegmental area (VTA) was shown to impair sociability in mice and weaken glutamatergic transmission in the same report. Previously it had been shown that Cbln1-null mice exhibit ataxia and abnormalities in synaptic integrity and plasticity in the cerebellum (Hirai et al., 2005). Furthermore, Otsuka et al., 2016 demonstrated that retention/retrieval of cued and contextual fear memory and spatial learning was impaired in forebrain-predominant Cbln1-null mice, whereas acquisition of fear memory was impaired in cerebellum-predominant Cbln1-null mice. CBLN1 binds to presynaptic NRXN1/2/3 and postsynaptic GRID1/2 to form trimolecular complexes that trans-synaptically organize glutamatergic synapse formation (Matsuda et al., 2010; Uemura et al., 2010).
Molecular Function
Required for synapse integrity and synaptic plasticity. During cerebellar synapse formation, essential for the formation and maintenance of parallel fiber and Purkinje cell synapses. When parallel fibers make contact with Purkinje spines, CBLN1 interaction with GRID2 triggers the recruitment of NRXN1 and secretory vesicles to the sites of contact. NRXN1-CBLN1-GRID2 signaling induces presynaptic morphological changes, which may further accumulate pre- and postsynaptic components to promote bidirectional maturation of parallel fiber - Purkinje cell functionally active synapses by a positive feedback mechanism.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1.
Cbln1 homozygous knockout mice exhibit ataxia, a waddling gait, decreased motor coordination but no tremors. Although gross cerebellar morphology is intact, there is a decrease in the number of synapses of parallel fibers on Purkinje neurons and an increased in the number of climbing fiber terminals on Purkinje neurons with no change in the inhibitory glutamatergic and glycinergic synapses. Cbln1 homozygous knockout mice exhibit abnormal dendritic spines, and decreased excitatory EPSCs although intrinsic membrane properties are not altered.
References
Type
Title
Author, Year
Primary
Cbln1 is essential for synaptic integrity and plasticity in the cerebellum.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Homozygous cbln1 null mice were generated by homologous recombination using an 11.57kb HindIII-BamHI fragment containing the entire cbln1 gene, 5kb 5' upstream sequence, 2kb 3' downstream sequence, a neomycin resistance cassette inserted downstream of the cbln1 start codon, and a Herpes simplex thymidine kinase cassette inserted downstream of the stop codon, resulting in the frameshift deletion from the third nucleotide of codon 28.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: AB2.2 primary ES cells
Model Source: 16234806
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Heterozygous cbln1 null mice were generated by homologous recombination using an 11.57kb HindIII-BamHI fragment containing the entire cbln1 gene, 5kb 5' upstream sequence, 2kb 3' downstream sequence, a neomycin resistance cassette inserted downstream of the cbln1 start codon, and a Herpes simplex thymidine kinase cassette inserted downstream of the stop codon, resulting in the frameshift deletion from the third nucleotide of codon28.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: AB2.2 primary ES cells
Model Source: 16234806
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 3 of the Cbln1 gene using CamkII-Cre, in excitatory neurons of the forebrain
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: CD-1
ES Cell Line: C57BL/6N
Mutant ES Cell Line: Model Source: 27852787
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 3 of the Cbln1 gene using Grin2C-cre knock-in mice (Miyazaki et al., 2012), predominantly in the granule neurons of the cerebellum
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: CD-1
ES Cell Line: C57BL/6N
Mutant ES Cell Line: Model Source: 27852787
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 1 -2 of the Cbln1 using Vglut2-cre, in Vglut2 expressing neurons of the thalamus, midbrain and brainstem.A viral vector containing the channel rhodopsin AAV-DIO-Chr2-eYFP was injected into the VTA of these Vglut2-Cbln1 conditional knockout mice as a reporter
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: FVB/NJ
ES Cell Line: Mutant ES Cell Line: Model Source: 20537373
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 1-2 from the Cbln1 gene using a AAV-cre, injected stereotaxically into the ventral tegmental area (VTA) bilaterally, age of injection not indicated in the article). To study the effect on glutamatergic trasmission following loss of Cbln1 in the VTA, the Cbln1 fl/fl mice were first crossed with Ai32 mice that contain the Cre inducible form of a light activated excitatory opsin- channel rhodopsin-2 enabling light induced activation of axon terminals of medium spiny neurons of the nucleus accumbens. All behavioral experiments were conducted approximately 20 days after the surgery required for injections.
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: FVB/NJ
ES Cell Line: Mutant ES Cell Line: Model Source: 28297715
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exon 1 and 2 of the Cbln1 gene, using AAV-cre containing Vglut2 promoter driven Cre, bilaterally injected into the ventral tegmental area, mice tested 28 days after injection of viral vector, age of injection not indicated in the article
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: FVB/NJ
ES Cell Line: Mutant ES Cell Line: Model Source: 28297715
Description: Homozygous cbln1 null mice climbing fibers synapse at both shaft dendrites and distal spiny branchlets in the cerebellum whereas in the wildtype mice climbing fibers synapse with shaft dendrites alone.
Exp Paradigm: Immunohistochemistry: vglut2 (climbing fiber)
Description: Homozygous cbln1 null mice showed reduced one-to-one innervation of purkinje neurons by climbing fibers compared to controls.
Exp Paradigm: Single clibing fiber epscs indicate establishment of single climbing fiber innervation of purkinje neurons.
Description: Homozygous cbln1 null mice showed decrease in the number of synapses of parallel fibers on purkinje neurons, compared to controls.
Exp Paradigm: NA
Description: Homozygous cbln1 null mice showed increased numbers of naked spines that contained postsynaptic densities but lacked presynaptic contacts, compared to controls. homozygous cbln1 null mice showed increased mismatch between the postsynaptic density and presynatptic elements at parallel fiber-purkinje cell synapses, compared to controls.
Exp Paradigm: NA
Description: Homozygous cbln1 null mice showed no ltd of parallel fiber epscs upon direct purkinje cell depolarization whereas control mice showed ltd using the same protocol. the lack of ltd in homozygous cbln1 null mice was not due to reduced initial parallel fiber epsc amplitudes as ltd could not be induced in mutants even when the initial parallel fiber epsc amplitudes were similar between mutants and controls.
Exp Paradigm: Climbing fiber stimulation was replaced by direct depolarisation of purkinje neurons to avoid climbing fiber-induced calcium spikes that enhance ltd induction.
Description: Homozygous cbln1 null mice showed slower rise times in climbing fibers with smaller epsc amplitudes, compared to controls. increasing stimulus intensity obliterated the slow rise times in homozygous cbln1 null mice.
Exp Paradigm: NA
Description: Homozygous cbln1 null mice showed no change electric shock threshold to elicit flinching response but showed lower threshold to elicit jumping and vocalization compared to controls, indicating a increased sensitivity to pain.
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of cue: short-term memory2
Decreased
Description: Homozygous cbln1 null mice showed decrease in freezing response to cue at 10 min post acquisition, compared to control. post hoc analysis comparing a sub-population of cbln1 mice showing more freezing response to a subpopulation of wildtype mice showing less freezing response, also showed a decrease in freezing response to cue at 10 min post acquisition in cbln1 null mice.
Exp Paradigm: Conditioned fear memory was evaluated by freezing responses 10 min after the acquisition trial by measuring freezing responses to the same cue.
Description: Homozygous cbln1 null mice showed decrease in freezing response during the acquisition phase of the fear conditioning test, compared to controls.
Exp Paradigm: Freezing response was recorded from 0 to 6mins during the acquisition phase.
Cued or contextual fear conditioning: memory of cue2
Decreased
Description: Homozygous cbln1 null mice showed decrease in freezing response to cue at 24 h post acquisition, compared to control. post hoc analysis comparing a sub-population of cbln1 mice showing more freezing response to a subpopulation of wildtype mice showing less freezing response, also showed a decrease in freezing response to cue at 24 h post acquisition in cbln1 null mice.
Exp Paradigm: Conditioned fear memory was evaluated by freezing responses 24 h after the acquisition trial by measuring freezing responses to the same cue.
Cued or contextual fear conditioning: memory of context: short-term memory2
Decreased
Description: Homozygous cbln1 null mice showed decrease in freezing response to context at 24 h post acquisition, compared to control. post hoc analysis comparing a sub-population of cbln1 mice showing more freezing response to a subpopulation of wildtype mice showing less freezing response, also showed a decrease in freezing response to context at 24hr post acquisition in cbln1 null mice.
Exp Paradigm: Conditioned fear memory was evaluated by freezing responses 24 h after the acquisition trial by measuring freezing responses to the same context.
Cued or contextual fear conditioning: memory of context2
Decreased
Description: Homozygous cbln1 null mice showed decrease in freezing response to context at 10 min post acquisition, compared to control. post hoc analysis comparing a sub-population of cbln1 mice that show more freezing response (as in wildtype controls) to a subpopulation of wildtype mice that show less freezing response, also showed a decrease in freezing response to context at 10 min post acquisition in cbln1 null mice, but this was not statistically significant.
Exp Paradigm: Conditioned fear memory was evaluated by freezing responses 10 min after the acquisition trial by measuring freezing responses to the same context.
Description: Homozygous cbln1 null mice showed a loss of cbln1 transcript, peptide and protein, compared to controls.
Exp Paradigm: Radioimmunoassay (ria)
Description: Heterozygous cbln1 null mice showed a loss of cbln1 transcript, peptide and protein, compared to controls.
Exp Paradigm: Radioimmunoassay (ria)
Cued or contextual fear conditioning: memory of cue1
Decreased
Description: Forebrain specific deletion of cbln1 in mice decreased freezing response to cue at 24 h post acquisition, compared to control.
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of context: short-term memory1
Decreased
Description: Forebrain specific deletion of cbln1 in mice decreased freezing response to context at 10 min post acquisition, compared to controls.
Exp Paradigm: NA
Description: Forebrain specific deletion of cbln1 in mice increased the number of errors when the platform was invisible, compared to controls.
Exp Paradigm: In a six arm radial maze, entries into arms without the platform were scored as errors.
Cued or contextual fear conditioning: memory of context1
Decreased
Description: Forebrain specific deletion of cbln1 in mice decreased freezing response to context at 24 h post acquisition, compared to controls.
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of cue: short-term memory1
Decreased
Description: Forebrain specific deletion of cbln1 in mice decreased freezing response to cue at 10 min post acquisition, compared to control.
Exp Paradigm: NA
Description: Forebrain specific deletion of cbln1 in mice showed reduced expression of cbln1 protein in the molecular layer of the dentate gyrus, the stratum lacunosum-moleculare of the hippocampus, and the rsg layer i of the cerebral cortex, compared to controls.
Exp Paradigm: NA
Description: Forebrain specific deletion of cbln1 in mice showed reduced expression of cbln1 protein in the molecular layer of the dentate gyrus, and the stratum lacunosum-moleculare of the hippocampus compared to controls.
Exp Paradigm: NA
Cued or contextual fear conditioning: memory of cue: short-term memory1
Decreased
Description: Cerebellum specific deletion of cbln1 in mice showed decrease in freezing response to cue at 10 min post acquisition, compared to control.
Exp Paradigm: Conditioned fear memory was evaluated by freezing responses 10 min after the acquisition trial by measuring freezing responses to the same cue.
Description: Cerebellum specific deletion of cbln1 in mice showed decrease in freezing response during the acquisition phase of the fear conditioning test, compared to controls. post hoc analysis comparing a sub-population of cbln1 mice that show more freezing response (as in wildtype controls) to a subpopulation of wildtype mice showed no change in freezing response at 10 min and 24 h post acquisition in cbln1 null mice, indicating that cerebellar cbln1 contributes to fear learning, particularly during the acquisition phase.
Exp Paradigm: Freezing response was recorded from 0 to 6mins during the acquisition phase.
Cued or contextual fear conditioning: memory of cue1
Decreased
Description: Cerebellum specific deletion of cbln1 in mice showed decrease in freezing response to cue at 24 h post acquisition, compared to control.
Exp Paradigm: Conditioned fear memory was evaluated by freezing responses 24 h after the acquisition trial by measuring freezing responses to the same cue.
Cued or contextual fear conditioning: memory of context: short-term memory1
Decreased
Description: Cerebellum specific deletion of cbln1 in mice showed decrease in freezing response to context at 10 min post acquisition, compared to control.
Exp Paradigm: Conditioned fear memory was evaluated by freezing responses 10 min after the acquisition trial by measuring freezing responses to the same context.
Cued or contextual fear conditioning: memory of context1
Decreased
Description: Cerebellum specific deletion of cbln1 in mice showed decrease in freezing response to context at 24 h post acquisition, compared to control.
Exp Paradigm: Conditioned fear memory was evaluated by freezing responses 24 h after the acquisition trial by measuring freezing responses to the same context.
Description: Cerebellum specific deletion of cbln1 reduced the expression of cbln1 protein in the cerebellum compared to controls. cerebellum specific deletion of cbln1 also reduced the expression of cbln1 protein in the rsg and cg layer i of the cerebral cortex at 3-5 months and in the rsg layer i but not the cg layer i at 1 month, compared to controls.
Exp Paradigm: NA
Description: Vglut cre-cbln1 cko mice injected with the light sensitive channelorhopsin chr2, showed reduced excitatory currents, evoked by light, in the nucleus accumbens
Exp Paradigm: NA
Description: Vglut cre-cbln1 cko mice show reduced time in contact with paired mouse in the reciprocal social interaction test, during which the number of usvs were assessed
Exp Paradigm: NA
Description: Vglut cre-cbln1 cko mice have impaired sociability in the three chamber social approach test and spend less time close to the chamber containing stimulus mouse as opposed to the empty cage
Exp Paradigm: NA
Ultrasonic vocalization: interaction induced: opposite sex stimulus1
Decreased
Description: Vglut cre-cbln1 cko mice have reduced number of usvs while interacting while interacting with genotype matched males as well
Exp Paradigm: NA
Description: Light-evoked excitatory postsynaptic currents (using the light-activated excitatory opsin crossed into the cbln1 fl/fl background) are reduced in the medium spiny neurons of the nucleus accumbens that are known targets of the ventral tegmental area in vta-cbln1 cko mice with cre injected into the vta
Exp Paradigm: NA
Description: Vglut2 neurons targeted deletions of cbln1 using cre under the vglut2 promotor, injected in cbln1 flf/fl mice via a viral vector into the vta, show impaired social approach to stimulus mouse compared to empty cage assessed by time spent sniffing
Exp Paradigm: NA
