Highlights • Proper connectivity of neuronal circuits require the function of glial cells. • Astrocytes and microglia control synapse formation, elimination and plasticity. • Synaptic and circuit ...plasticity is regulated by astrocytes and microglia. • Neurological disorders may arise through aberrant glia–neuron communication.
Astrocytes are complex glial cells with numerous fine cellular processes that infiltrate the neuropil and interact with synapses. The mechanisms that control the establishment of astrocyte morphology ...are unknown, and it is unclear whether impairing astrocytic infiltration of the neuropil alters synaptic connectivity. Here we show that astrocyte morphogenesis in the mouse cortex depends on direct contact with neuronal processes and occurs in parallel with the growth and activity of synaptic circuits. The neuroligin family cell adhesion proteins NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, the formation and function of cortical excitatory synapses are diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a previously undescribed mechanism of action for neuroligins and link astrocyte morphogenesis to synaptogenesis. Because neuroligin mutations have been implicated in various neurological disorders, these findings also point towards an astrocyte-based mechanism of neural pathology.
Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic ...adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism.
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•Astrocyte-secreted hevin is a pre- and postsynaptic organizer•Hevin induces thalamocortical synapse formation by bridging NRX1α and NL1•Hevin is required for recruitment of NL1 and NMDAR to excitatory synapses in vivo•Astrocyte-secreted hevin is necessary for ocular dominance plasticity
Astrocytes promote synapse formation and plasticity by secreting a protein that bridges non-interacting isoforms of neurexin and neuroligin, suggesting an additional layer of complexity to the isoform code that dictates synaptic adhesion.
The Cre-loxP system is invaluable for spatial and temporal control of gene knockout, knockin, and reporter expression in the mouse nervous system. However, we report varying probabilities of ...unexpected germline recombination in distinct Cre driver lines designed for nervous system-specific recombination. Selective maternal or paternal germline recombination is showcased with sample Cre lines. Collated data reveal germline recombination in over half of 64 commonly used Cre driver lines, in most cases with a parental sex bias related to Cre expression in sperm or oocytes. Slight differences among Cre driver lines utilizing common transcriptional control elements affect germline recombination rates. Specific target loci demonstrated differential recombination; thus, reporters are not reliable proxies for another locus of interest. Similar principles apply to other recombinase systems and other genetically targeted organisms. We hereby draw attention to the prevalence of germline recombination and provide guidelines to inform future research for the neuroscience and broader molecular genetics communities.
•Most mouse Cre driver lines tested exhibited variable rates of germline recombination•Germline recombination exhibits parental sex bias and target locus selectivity•Similar principles apply to multiple organisms and recombinase systems•Guidelines are provided for detecting and minimizing unwanted germline recombination
Luo et al. report variable rates of germline recombination in commonly used mouse Cre driver lines, influenced by sex of Cre-carrying parents and target loci. Guidelines are provided to optimize cell-type-specific recombination in genetically targeted organisms expressing site-specific recombinases.
The Cre-loxP system is invaluable for spatial and temporal control of gene knockout, knockin, and reporter expression in the mouse nervous system. However, we report varying probabilities of ...unexpected germline recombination in distinct Cre driver lines designed for nervous system-specific recombination. Selective maternal or paternal germline recombination is showcased with sample Cre lines. Collated data reveal germline recombination in over half of 64 commonly used Cre driver lines, in most cases with a parental sex bias related to Cre expression in sperm or oocytes. Slight differences among Cre driver lines utilizing common transcriptional control elements affect germline recombination rates. Specific target loci demonstrated differential recombination; thus, reporters are not reliable proxies for another locus of interest. Similar principles apply to other recombinase systems and other genetically targeted organisms. We hereby draw attention to the prevalence of germline recombination and provide guidelines to inform future research for the neuroscience and broader molecular genetics communities.
Luo et al. report variable rates of germline recombination in commonly used mouse Cre driver lines, influenced by sex of Cre-carrying parents and target loci. Guidelines are provided to optimize cell-type-specific recombination in genetically targeted organisms expressing site-specific recombinases.
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