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      Cytosolic PSD-95 interactor alters functional organization of neural circuits and AMPA receptor signaling independent of PSD-95 binding

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          Abstract

          Cytosolic PSD-95 interactor (cypin) regulates many aspects of neuronal development and function, ranging from dendritogenesis to synaptic protein localization. While it is known that removal of postsynaptic density protein-95 (PSD-95) from the postsynaptic density decreases synaptic N-methyl-D-aspartate (NMDA) receptors and that cypin overexpression protects neurons from NMDA-induced toxicity, little is known about cypin’s role in AMPA receptor clustering and function. Experimental work shows that cypin overexpression decreases PSD-95 levels in synaptosomes and the PSD, decreases PSD-95 clusters/μm 2, and increases mEPSC frequency. Analysis of microelectrode array (MEA) data demonstrates that cypin or cypinΔPDZ overexpression increases sensitivity to CNQX (cyanquixaline) and AMPA receptor-mediated decreases in spike waveform properties. Network-level analysis of MEA data reveals that cypinΔPDZ overexpression causes networks to be resilient to CNQX-induced changes in local efficiency. Incorporating these findings into a computational model of a neural circuit demonstrates a role for AMPA receptors in cypin-promoted changes to networks and shows that cypin increases firing rate while changing network functional organization, suggesting cypin overexpression facilitates information relay but modifies how information is encoded among brain regions. Our data show that cypin promotes changes to AMPA receptor signaling independent of PSD-95 binding, shaping neural circuits and output to regions beyond the hippocampus.

          Author Summary

          We used lentivirus to overexpress cytosolic PSD-95 interactor (cypin) and a cypin mutant that cannot bind PSD-95 (cypinΔPDZ) to understand how cypin regulates synaptic signaling. Using biochemical and electrophysiological approaches, we show that cypin, but not the cypin mutant, regulates synaptic PSD-95 content. Surprisingly, cypin overexpression increases AMPA receptor function independent of its role in PSD-95 localization, while cypinΔPDZ overexpression causes networks to be resistant to CNQX-mediated changes to local efficiency. We then developed a computational model to account for the effects of cypin overexpression, finding that our simulated model also demonstrates a role for AMPA receptors in cypin-promoted changes to neural circuits. These results support a role for cypin in controlling synaptic function at synapses that is distinct from regulation of PSD-95 function.

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              Numerous studies have examined the neuronal inputs and outputs of many areas within the mammalian cerebral cortex, but how these areas are organized into neural networks that communicate across the entire cortex is unclear. Over 600 labeled neuronal pathways acquired from tracer injections placed across the entire mouse neocortex enabled us to generate a cortical connectivity atlas. A total of 240 intracortical connections were manually reconstructed within a common neuroanatomic framework, forming a cortico-cortical connectivity map that facilitates comparison of connections from different cortical targets. Connectivity matrices were generated to provide an overview of all intracortical connections and subnetwork clusterings. The connectivity matrices and cortical map revealed that the entire cortex is organized into four somatic sensorimotor, two medial, and two lateral subnetworks that display unique topologies and can interact through select cortical areas. Together, these data provide a resource that can be used to further investigate cortical networks and their corresponding functions. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Netw Neurosci
                Netw Neurosci
                netn
                Network Neuroscience
                MIT Press (One Rogers Street, Cambridge, MA 02142-1209USAjournals-info@mit.edu )
                2472-1751
                2021
                2021
                : 5
                : 1
                : 166-197
                Affiliations
                [1]Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
                [2]Biomedical Engineering Graduate Program, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
                [3]Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
                [4]Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
                [5]Biomedical Engineering Graduate Program, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
                [6]Institute for Physical Science and Technology, University of Maryland, College Park, MD, USA
                [7]Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
                [8]Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, New Brunswick, NJ, USA
                [9]Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
                [10]Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
                [11]Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
                [12]Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
                [13]Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
                [14]Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA
                [15]Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                [†]

                A. R. Rodriguez, E. D. Anderson, and K. M. O’Neill contributed equally to this work.

                Handling Editor: Olaf Sporns

                Author information
                https://orcid.org/0000-0002-2591-9393
                https://orcid.org/0000-0003-0575-6707
                https://orcid.org/0000-0003-4397-5767
                https://orcid.org/0000-0002-7702-070X
                https://orcid.org/0000-0003-0540-4816
                https://orcid.org/0000-0003-2191-8550
                https://orcid.org/0000-0002-0954-4122
                https://orcid.org/0000-0002-1679-3565
                Article
                netn_a_00173
                10.1162/netn_a_00173
                7935033
                33688611
                fc553916-3f57-4616-91a7-d0d5022ddd51
                © 2020 Massachusetts Institute of Technology

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. For a full description of the license, please visit https://creativecommons.org/licenses/by/4.0/legalcode.

                History
                : 13 July 2020
                : 26 October 2020
                Page count
                Figures: 13, Tables: 1, Equations: 1, References: 75, Pages: 32
                Funding
                Funded by: Division of Integrative Organismal Systems, FundRef http://dx.doi.org/10.13039/100000154;
                Award ID: IOS-1353724
                Funded by: New Jersey Commission on Brain Injury Research, FundRef http://dx.doi.org/10.13039/100008474;
                Award ID: CBIR14IRG019
                Funded by: National Institute of General Medical Sciences, FundRef http://dx.doi.org/10.13039/100000057;
                Award ID: T32 GM008339-20
                Funded by: National Institute of General Medical Sciences, FundRef http://dx.doi.org/10.13039/100000057;
                Award ID: T32 GM008339-20
                Funded by: National Institute of General Medical Sciences, FundRef http://dx.doi.org/10.13039/100000057;
                Award ID: T32 GM008339-20
                Funded by: New Jersey Commission on Brain Injury Research, FundRef http://dx.doi.org/10.13039/100008474;
                Award ID: CBIR14IRG019
                Funded by: New Jersey Commission on Brain Injury Research, FundRef http://dx.doi.org/10.13039/100008474;
                Award ID: CBIR13FEL002
                Funded by: New Jersey Commission on Brain Injury Research, FundRef http://dx.doi.org/10.13039/100008474;
                Award ID: CBIR16FEL013
                Funded by: U.S. Department of Education, FundRef http://dx.doi.org/10.13039/100000138;
                Award ID: P200A150131
                Funded by: Rutgers, The State University of New Jersey, FundRef http://dx.doi.org/10.13039/100011132;
                Award ID: Rutgers University School of Arts and Sciences Honors Program Research Fellowship
                Funded by: New Jersey Commission on Brain Injury Research, FundRef http://dx.doi.org/10.13039/100008474;
                Award ID: CBIR20IRG003
                Funded by: New Jersey Commission on Brain Injury Research, FundRef http://dx.doi.org/10.13039/100008474;
                Award ID: CBIR20IRG003
                Categories
                Research Article
                Custom metadata
                Rodriguez, A. R., Anderson, E. D., O’Neill, K. M., McEwan, P. P., Vigilante, N. F., Kwon, M., Akum, B. F., Stawicki, T. M., Meaney. D. F., & Firestein, B. L. (2021). Cytosolic PSD-95 interactor alters functional organization of neural circuits and AMPA receptor signaling independent of PSD-95 binding. Network Neuroscience, 5(1), 166–197. https://doi.org/10.1162/netn_a_00173

                cypin,ampa receptors,microelectrode array,electrophysiology,hippocampal neurons,neural circuits

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