{"doi":"10.1523/jneurosci.0375-15.2016","title":"Cell Type-Specific Circuit Mapping Reveals the Presynaptic Connectivity of Developing Cortical Circuits","abstract":"<jats:p>The mammalian cerebral cortex is a dense network composed of local, subcortical, and intercortical synaptic connections. As a result, mapping cell type-specific neuronal connectivity in the cerebral cortex<jats:italic>in vivo</jats:italic>has long been a challenge for neurobiologists. In particular, the development of excitatory and inhibitory interneuron presynaptic input has been hard to capture. We set out to analyze the development of this connectivity in the first postnatal month using a murine model. First, we surveyed the connectivity of one of the earliest populations of neurons in the brain, the Cajal-Retzius (CR) cells in the neocortex, which are known to be critical for cortical layer formation and are hypothesized to be important in the establishment of early cortical networks. We found that CR cells receive inputs from deeper-layer excitatory neurons and inhibitory interneurons in the first postnatal week. We also found that both excitatory pyramidal neurons and inhibitory interneurons received broad inputs in the first postnatal week, including inputs from CR cells. Expanding our analysis into the more mature brain, we assessed the inputs onto inhibitory interneurons and excitatory projection neurons, labeling neuronal progenitors with Cre drivers to study discrete populations of neurons in older cortex, and found that excitatory cortical and subcortical inputs are refined by the fourth week of development, whereas local inhibitory inputs increase during this postnatal period. Cell type-specific circuit mapping is specific, reliable, and effective, and can be used on molecularly defined subtypes to determine connectivity in the cortex.</jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT</jats:bold>Mapping cortical connectivity in the developing mammalian brain has been an intractable problem, in part because it has not been possible to analyze connectivity with cell subtype precision. Our study systematically targets the presynaptic connections of discrete neuronal subtypes in both the mature and developing cerebral cortex. We analyzed the connections that Cajal-Retzius cells make and receive, and found that these cells receive inputs from deeper-layer excitatory neurons and inhibitory interneurons in the first postnatal week. We assessed the inputs onto inhibitory interneurons and excitatory projection neurons, the major two types of neurons in the cortex, and found that excitatory inputs are refined by the fourth week of development, whereas local inhibitory inputs increase during this postnatal period.</jats:p>","journal":"The Journal of Neuroscience","year":2016,"id":629453,"datarank":0.47032413238937254,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"self_citation_contribution":0.47032413238937254,"citation_network_contribution":0.0,"self_endowment_contribution":0.47032413238937254,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1630180,"name":"Gloria Fernandez","orcid":null,"position":1,"is_corresponding":false},{"id":814755,"name":"Mariya Barch","orcid":null,"position":2,"is_corresponding":false},{"id":1630181,"name":"Jason Doll","orcid":null,"position":3,"is_corresponding":false},{"id":1630182,"name":"Ivan Zamora Diaz","orcid":null,"position":4,"is_corresponding":false},{"id":393421,"name":"Samuel J. Pleasure","orcid":"0000-0001-8599-1613","position":5,"is_corresponding":false},{"id":1630179,"name":"Laura A. Cocas","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Cell Type-Specific Circuit Mapping Reveals the Presynaptic Connectivity of Developing Cortical Circuits","abstract":"<jats:p>The mammalian cerebral cortex is a dense network composed of local, subcortical, and intercortical synaptic connections. As a result, mapping cell type-specific neuronal connectivity in the cerebral cortex<jats:italic>in vivo</jats:italic>has long been a challenge for neurobiologists. In particular, the development of excitatory and inhibitory interneuron presynaptic input has been hard to capture. We set out to analyze the development of this connectivity in the first postnatal month using a murine model. First, we surveyed the connectivity of one of the earliest populations of neurons in the brain, the Cajal-Retzius (CR) cells in the neocortex, which are known to be critical for cortical layer formation and are hypothesized to be important in the establishment of early cortical networks. We found that CR cells receive inputs from deeper-layer excitatory neurons and inhibitory interneurons in the first postnatal week. We also found that both excitatory pyramidal neurons and inhibitory interneurons received broad inputs in the first postnatal week, including inputs from CR cells. Expanding our analysis into the more mature brain, we assessed the inputs onto inhibitory interneurons and excitatory projection neurons, labeling neuronal progenitors with Cre drivers to study discrete populations of neurons in older cortex, and found that excitatory cortical and subcortical inputs are refined by the fourth week of development, whereas local inhibitory inputs increase during this postnatal period. Cell type-specific circuit mapping is specific, reliable, and effective, and can be used on molecularly defined subtypes to determine connectivity in the cortex.</jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT</jats:bold>Mapping cortical connectivity in the developing mammalian brain has been an intractable problem, in part because it has not been possible to analyze connectivity with cell subtype precision. Our study systematically targets the presynaptic connections of discrete neuronal subtypes in both the mature and developing cerebral cortex. We analyzed the connections that Cajal-Retzius cells make and receive, and found that these cells receive inputs from deeper-layer excitatory neurons and inhibitory interneurons in the first postnatal week. We assessed the inputs onto inhibitory interneurons and excitatory projection neurons, the major two types of neurons in the cortex, and found that excitatory inputs are refined by the fourth week of development, whereas local inhibitory inputs increase during this postnatal period.</jats:p>","is_dataset_classified":null,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"26985044","pmcid":"PMC4792945","openalex_id":"https://openalex.org/W2297138331","authors":[],"funders":[{"funder_name":"NIMH NIH HHS","grant_id":"R01 MH105360","title":null},{"funder_name":"NIMH NIH HHS","grant_id":"R01 MH077694","title":null}],"total_grants":2,"fwci":0.6,"citation_percentile":0.66232816,"influential_citations":0,"citation_trend":[{"year":2016,"count":1},{"year":2018,"count":2},{"year":2019,"count":1},{"year":2020,"count":6},{"year":2021,"count":3},{"year":2022,"count":1},{"year":2023,"count":4},{"year":2024,"count":2},{"year":2026,"count":2}],"oa_status":"bronze","license":"https://creativecommons.org/licenses/by-nc-sa/4.0/","oa_locations":[{"url":"https://www.jneurosci.org/content/jneuro/36/11/3378.full.pdf","host_type":"journal"},{"url":"https://www.jneurosci.org/content/jneuro/36/11/3378.full.pdf","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1523/JNEUROSCI.0375-15.2016","host_type":"publisher"},{"url":"https://doi.org/10.1523/jneurosci.0375-15.2016","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/26985044","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4792945","host_type":"repository"}],"fields_of_study":["Neural dynamics and brain function","Neurogenesis and neuroplasticity mechanisms","Neuroscience and Neuropharmacology Research"],"mesh_terms":["Age Factors","Animals","Animals, Newborn","Brain Mapping","Cerebral Cortex","Embryo, Mammalian","Female","Interneurons","Luminescent Proteins","Male","Mice, Transgenic","Nerve Net","Nerve Tissue Proteins","Neurons","Transduction, Genetic","Viral Envelope Proteins","Presynaptic Terminals","Organogenesis","Mice"],"keywords":["Neuroscience","Neocortex","Inhibitory postsynaptic potential","Excitatory postsynaptic potential","Interneuron","Biology","Cerebral cortex","Cortex (anatomy)","Barrel cortex","Sensory system","Interneurons","Cajal-retzius Cells","Circuit Development","Neuronal Connectivity","Viral Circuit Tracing"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-05T18:42:11.690629Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}