{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:16:50Z","timestamp":1790813810769,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T00:00:00Z","timestamp":1635984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT155959, PJT168922"],"award-info":[{"award-number":["PJT155959, PJT168922"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>P21-activated kinase 3 (PAK3) gene mutations are linked to several neurodevelopmental disorders, but the underlying mechanisms remain unclear. In this study, we used a tetracycline-inducible system to control the expression of a mutant PAK3 (mPAK3) protein in immediate early gene, namely cFos, positive cells to disrupt PAK signaling, specifically in cells activated by social interaction in transgenic mice. We show that the expression of mPAK3-GFP proteins was in cFos-expressing excitatory and inhibitory neurons in various brain regions, such as the cortex and hippocampus, commonly activated during learning and memory. Basal expression of mPAK3-GFP proteins in cFos-positive cells resulted in social recognition memory deficits in the three-chamber social interaction test, without affecting locomotor activity or other forms of memory. The social memory deficit was rescued by doxycycline to halt the mPAK3-GFP transgene expression. In addition, we show that the expression of mPAK3-GFP proteins in a subset of cFos-positive cells, induced by an antecedent short social interaction, termed social pairing, was sufficient to impair social recognition memory. These results indicate that normal PAK signaling in cFos-positive cells activated during social interaction is critical for social memory.<\/jats:p>","DOI":"10.3390\/cells10113010","type":"journal-article","created":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T09:11:32Z","timestamp":1636017092000},"page":"3010","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Disruption of PAK3 Signaling in Social Interaction Induced cFos Positive Cells Impairs Social Recognition Memory"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3481-6270","authenticated-orcid":false,"given":"Susan","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada"},{"name":"Department of Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengping","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada"},{"name":"Department of Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1037\/0003-066X.44.2.120","article-title":"Social Relationships and Their Developmental Significance","volume":"44","author":"Hartup","year":"1989","journal-title":"Am. Psychol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1037\/0003-066X.59.8.676","article-title":"Social Relationships and Health","volume":"59","author":"Cohen","year":"2004","journal-title":"Am. Psychol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1073\/pnas.1511085112","article-title":"Social Relationships and Physiological Determinants of Longevity across the Human Life Span","volume":"113","author":"Yang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1111\/j.1365-2788.2011.01446.x","article-title":"Social Integration of People with Intellectual Disability: Insights from a Social Psychological Research Programme","volume":"55","author":"Dijker","year":"2011","journal-title":"J. Intellect. Disabil. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/nrn4005","article-title":"Social Cognition in Schizophrenia","volume":"16","author":"Green","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1146\/annurev-psych-010416-044046","article-title":"The Structure of Social Cognition: In(Ter)Dependence of Sociocognitive Processes","volume":"68","author":"Cook","year":"2017","journal-title":"Annu. Rev. Psychol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1007\/s11689-010-9055-2","article-title":"The Genetic Basis of Non-Syndromic Intellectual Disability: A Review","volume":"2","author":"Kaufman","year":"2010","journal-title":"J. Neurodev. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1111\/cge.13698","article-title":"Non-Syndromic X Linked Intellectual Disability: Current Knowledge in Light of the Recent Advances in Molecular and Functional Studies","volume":"97","author":"Tejada","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/1675","article-title":"PAK3 Mutation in Nonsyndromic X-Linked Mental Retardation","volume":"20","author":"Allen","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1002\/1096-8628(20000814)93:4<294::AID-AJMG8>3.0.CO;2-F","article-title":"Missense Mutation in PAK3, R67C, Causes X-Linked Nonspecific Mental Retardation","volume":"93","author":"Bienvenu","year":"2000","journal-title":"Am. J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3607","DOI":"10.1093\/hmg\/ddu070","article-title":"A Mutation in PAK3 with a Dual Molecular Effect Deregulates the RAS\/MAPK Pathway and Drives an X-Linked Syndromic Phenotype","volume":"23","author":"Magini","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.neuron.2004.05.003","article-title":"Altered Cortical Synaptic Morphology and Impaired Memory Consolidation in Forebrain-Specific Dominant-Negative PAK Transgenic Mice","volume":"42","author":"Hayashi","year":"2004","journal-title":"Neuron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6641","DOI":"10.1523\/JNEUROSCI.0028-05.2005","article-title":"Abnormal Long-Lasting Synaptic Plasticity and Cognition in Mice Lacking the Mental Retardation Gene Pak3","volume":"25","author":"Meng","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"21497","DOI":"10.1074\/jbc.M703298200","article-title":"The P21-Activated Kinase 3 Implicated in Mental Retardation Regulates Spine Morphogenesis Through a Cdc42-Dependent Pathway","volume":"282","author":"Kreis","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1093\/hmg\/ddz296","article-title":"The Intellectual Disability PAK3 R67C Mutation Impacts Cognitive Functions and Adult Hippocampal Neurogenesis","volume":"29","author":"Castillon","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1128\/MCB.00969-10","article-title":"P21-Activated Kinases 1 and 3 Control Brain Size through Coordinating Neuronal Complexity and Synaptic Properties","volume":"31","author":"Huang","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1016\/j.celrep.2018.04.073","article-title":"Activation of Entorhinal Cortical Projections to the Dentate Gyrus Underlies Social Memory Retrieval Article Activation of Entorhinal Cortical Projections to the Dentate Gyrus Underlies Social Memory Retrieval","volume":"23","author":"Leung","year":"2018","journal-title":"Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"22393","DOI":"10.1074\/jbc.274.32.22393","article-title":"A Tyrosine-Phosphorylated Protein That Binds to an Important Regulatory Region on the Cool Family of P21-Activated Kinase-Binding Proteins","volume":"274","author":"Bagrodia","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5883","DOI":"10.1073\/pnas.1518382112","article-title":"Regulation of AMPA Receptor Subunit GluA1 Surface Expression by PAK3 Phosphorylation","volume":"112","author":"Hussain","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.gene.2016.12.014","article-title":"Structure, Biochemistry, and Biology of PAK Kinases","volume":"605","author":"Kumar","year":"2017","journal-title":"Gene"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25070","DOI":"10.1074\/jbc.270.42.25070","article-title":"Molecular Cloning of a New Member of the P21-Cdc42\/Rac-Activated Kinase (PAK) Family","volume":"270","author":"Manser","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0960-9822(00)00359-6","article-title":"Regulation of the Protein Kinase Raf-1 by Oncogenic Ras through Phosphatidylinositol 3-Kinase, Cdc42\/Rac and Pak","volume":"10","author":"Sun","year":"2000","journal-title":"Curr. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"40044","DOI":"10.1074\/jbc.M111.262246","article-title":"P21-Activated Kinase 3 (PAK3) Protein Regulates Synaptic Transmission through Its Interaction with the Nck2\/Grb4 Protein Adaptor","volume":"286","author":"Moreau","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"39600","DOI":"10.1074\/jbc.M105080200","article-title":"Dual Regulation of Mammalian Myosin VI Motor Function","volume":"276","author":"Yoshimura","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"30084","DOI":"10.1074\/jbc.M112.355073","article-title":"The P21-Activated Kinase PAK3 Forms Heterodimers With PAK1 in Brain Implementing Trans-Regulation of PAK3 Activity","volume":"287","author":"Combeau","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/hipo.20451","article-title":"Distinct, but Compensatory Roles of PAK1 and PAK3 in Spine Morphogenesis","volume":"18","author":"Boda","year":"2008","journal-title":"Hippocampus"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10816","DOI":"10.1523\/JNEUROSCI.2931-04.2004","article-title":"The Mental Retardation Protein PAK3 Contributes to Synapse Formation and Plasticity in Hippocampus","volume":"24","author":"Boda","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1111\/j.1471-4159.2008.05474.x","article-title":"The Four Mammalian Splice Variants Encoded by the P21-Activated Kinase 3 Gene Have Different Biological Properties","volume":"106","author":"Kreis","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/s41586-018-0191-2","article-title":"Parallel Emergence of Stable and Dynamic Memory Engrams in the Hippocampus","volume":"558","author":"Hainmueller","year":"2018","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1126\/science.aam6808","article-title":"Engrams and Circuits Crucial for Systems Consolidation of a Memory","volume":"356","author":"Kitamura","year":"2017","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.tins.2018.10.005","article-title":"Molecular Mechanisms of the Memory Trace","volume":"42","author":"Asok","year":"2019","journal-title":"Trends Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/35021052","article-title":"Fear Memories Require Protein Synthesis in the Amygdala for Reconsolidation after Retrieval","volume":"406","author":"Nader","year":"2000","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.conb.2015.07.009","article-title":"Memory Engram Storage and Retrieval","volume":"35","author":"Tonegawa","year":"2015","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1756-6606-5-32","article-title":"Catching the Engram: Strategies to Examine the Memory Trace","volume":"5","author":"Sakaguchi","year":"2012","journal-title":"Mol. Brain"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"20130161","DOI":"10.1098\/rstb.2013.0161","article-title":"The Search for a Hippocampal Engram","volume":"369","author":"Mayford","year":"2014","journal-title":"Philos. Trans. R. Soc. B"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/BF02935553","article-title":"The Role of Immediate Early Genes in the Stabilization of Long-Term Potentiation","volume":"5","author":"Abraham","year":"1991","journal-title":"Mol. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1006\/frne.1993.1006","article-title":"C-Fos and Related Immediate Early Gene Products as Markers of Activity in Neuroendocrine Systems","volume":"14","author":"Hoffman","year":"1993","journal-title":"Front. Neuroendocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.bbr.2013.04.048","article-title":"Mapping Memory Function in the Medial Temporal Lobe with the Immediate-Early Gene Arc","volume":"254","author":"Sauvage","year":"2013","journal-title":"Behav. Brain Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1126\/science.1214985","article-title":"Generation of a Synthetic Memory Trace","volume":"335","author":"Garner","year":"2012","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1126\/science.1143839","article-title":"Localization of a Stable Neural Correlate of Associative Memory","volume":"317","author":"Reijmers","year":"2007","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3744","DOI":"10.1038\/s41467-020-17560-3","article-title":"Neuroligin 2 Regulates Absence Seizures and Behavioral Arrests through GABAergic Transmission within the Thalamocortical Circuitry","volume":"11","author":"Cao","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_42","first-page":"1","article-title":"Simple Behavioral Assessment of Mouse Olfaction","volume":"8","author":"Yang","year":"2009","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/nprot.2006.116","article-title":"Morris Water Maze: Procedures for Assessing Spatial and Related Forms of Learning and Memory","volume":"1","author":"Vorhees","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41593-017-0030-z","article-title":"The C-Terminal Tails of Endogenous GluA1 and GluA2 Differentially Contribute to Hippocampal Synaptic Plasticity and Learning","volume":"21","author":"Zhou","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_45","unstructured":"Curzon, P., Rustay, N.R., and Browman, K.E. (2000). Cued and contextual fear conditioning for rodents. Methods of Behavior Analysis in Neuroscience, CRC Press\/Taylor & Francis. [2nd ed.]."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3848","DOI":"10.1523\/JNEUROSCI.6038-11.2012","article-title":"Spatial Firing Correlates of Physiologically Distinct Cell Types of the Rat Dentate Gyrus","volume":"32","author":"Neunuebel","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e20252","DOI":"10.7554\/eLife.20252","article-title":"Sparse Activity of Identified Dentate Granule Cells during Spatial Exploration","volume":"5","author":"Diamantaki","year":"2016","journal-title":"Elife"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S0076-6879(00)27292-3","article-title":"Tet Repressor-Based System for Regulated Gene Expression in Eukaryotic Cells: Principles and Advances","volume":"327","author":"Baron","year":"2000","journal-title":"Methods Enzymol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s11248-013-9767-7","article-title":"Inducible, Tightly Regulated and Non-Leaky Neuronal Gene Expression in Mice","volume":"23","author":"Delerue","year":"2014","journal-title":"Transgenic Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.neubiorev.2005.06.005","article-title":"Neural Circuits and Mechanisms Involved in Pavlovian Fear Conditioning: A Critical Review","volume":"30","author":"Kim","year":"2006","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.cell.2017.07.013","article-title":"Distinct Neural Circuits for the Formation and Retrieval of Episodic Memories","volume":"170","author":"Roy","year":"2017","journal-title":"Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1126\/science.aaf7003","article-title":"Ventral CA1 Neurons Store Social Memory","volume":"353","author":"Okuyama","year":"2016","journal-title":"Science"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3010\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:25:40Z","timestamp":1760167540000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3010"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,4]]},"references-count":52,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cells10113010"],"URL":"https:\/\/doi.org\/10.3390\/cells10113010","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,4]]}}}