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Establishment of high reciprocal connectivity between clonal cortical neurons is regulated by the Dnmt3b DNA methyltransferase and clustered protocadherins.

ABSTRACT: The specificity of synaptic connections is fundamental for proper neural circuit function. Specific neuronal connections that underlie information processing in the sensory cortex are initially established without sensory experiences to a considerable extent, and then the connections are individually refined through sensory experiences. Excitatory neurons arising from the same single progenitor cell are preferentially connected in the postnatal cortex, suggesting that cell lineage contributes to the initial wiring of neurons. However, the postnatal developmental process of lineage-dependent connection specificity is not known, nor how clonal neurons, which are derived from the same neural stem cell, are stamped with the identity of their common neural stem cell and guided to form synaptic connections.We show that cortical excitatory neurons that arise from the same neural stem cell and reside within the same layer preferentially establish reciprocal synaptic connections in the mouse barrel cortex. We observed a transient increase in synaptic connections between clonal but not nonclonal neuron pairs during postnatal development, followed by selective stabilization of the reciprocal connections between clonal neuron pairs. Furthermore, we demonstrate that selective stabilization of the reciprocal connections between clonal neuron pairs is impaired by the deficiency of DNA methyltransferase 3b (Dnmt3b), which determines DNA-methylation patterns of genes in stem cells during early corticogenesis. Dnmt3b regulates the postnatal expression of clustered protocadherin (cPcdh) isoforms, a family of adhesion molecules. We found that cPcdh deficiency in clonal neuron pairs impairs the whole process of the formation and stabilization of connections to establish lineage-specific connection reciprocity.Our results demonstrate that local, reciprocal neural connections are selectively formed and retained between clonal neurons in layer 4 of the barrel cortex during postnatal development, and that Dnmt3b and cPcdhs are required for the establishment of lineage-specific reciprocal connections. These findings indicate that lineage-specific connection reciprocity is predetermined by Dnmt3b during embryonic development, and that the cPcdhs contribute to postnatal cortical neuron identification to guide lineage-dependent synaptic connections in the neocortex.

SUBMITTER: Tarusawa E

PROVIDER: S-EPMC5133762 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Establishment of high reciprocal connectivity between clonal cortical neurons is regulated by the Dnmt3b DNA methyltransferase and clustered protocadherins.

Tarusawa Etsuko E Sanbo Makoto M Okayama Atsushi A Miyashita Toshio T Kitsukawa Takashi T Hirayama Teruyoshi T Hirabayashi Takahiro T Hasegawa Sonoko S Kaneko Ryosuke R Toyoda Shunsuke S Kobayashi Toshihiro T Kato-Itoh Megumi M Nakauchi Hiromitsu H Hirabayashi Masumi M Yagi Takeshi T Yoshimura Yumiko Y

BMC biology 20161202 1

<h4>Background</h4>The specificity of synaptic connections is fundamental for proper neural circuit function. Specific neuronal connections that underlie information processing in the sensory cortex are initially established without sensory experiences to a considerable extent, and then the connections are individually refined through sensory experiences. Excitatory neurons arising from the same single progenitor cell are preferentially connected in the postnatal cortex, suggesting that cell lin ...[more]

PMID: 27912755

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Project description:Neuronal identity is generated by the cell-surface expression of clustered protocadherin (Pcdh) isoforms. In mice, 58 isoforms from three gene clusters, Pcdhα, Pcdhβ, and Pcdhγ, are differentially expressed in neurons. Since cis-heteromeric Pcdh oligomers on the cell surface interact homophilically with that in other neurons in trans, it has been thought that the Pcdh isoform repertoire determines the binding specificity of synapses. We previously described the cooperative functions of isoforms from all three Pcdh gene clusters in neuronal survival and synapse formation in the spinal cord. However, the neuronal loss and the following neonatal lethality prevented an analysis of the postnatal development and characteristics of the clustered-Pcdh-null (Δαβγ) neural circuits. Here, we used two methods, one to generate the chimeric mice that have transplanted Δαβγ neurons into mouse embryos, and the other to generate double mutant mice harboring null alleles of both the Pcdh gene and the proapoptotic gene Bax to prevent neuronal loss. First, our results showed that the surviving chimeric mice that had a high contribution of Δαβγ cells exhibited paralysis and died in the postnatal period. An analysis of neuronal survival in postnatally developing brain regions of chimeric mice clarified that many Δαβγ neurons in the forebrain were spared from apoptosis, unlike those in the reticular formation of the brainstem. Second, in Δαβγ/Bax null double mutants, the central pattern generator (CPG) for locomotion failed to create a left-right alternating pattern even in the absence of neurodegeneraton. Third, calcium imaging of cultured hippocampal neurons showed that the network activity of Δαβγ neurons tended to be more synchronized and lost the variability in the number of simultaneously active neurons observed in the control network. Lastly, a comparative analysis for trans-homophilic interactions of the exogenously introduced single Pcdh-γA3 isoforms between the control and the Δαβγ neurons suggested that the isoform-specific trans-homophilic interactions require a complete match of the expressed isoform repertoire at the contacting sites between interactive neurons. These results suggested that combinations of clustered Pcdh isoforms are required for building appropriate neural circuits.

Dataset Information

Establishment of high reciprocal connectivity between clonal cortical neurons is regulated by the Dnmt3b DNA methyltransferase and clustered protocadherins.

Publications

Establishment of high reciprocal connectivity between clonal cortical neurons is regulated by the Dnmt3b DNA methyltransferase and clustered protocadherins.

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