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LRRK2 mutation alters behavioral, synaptic, and nonsynaptic adaptations to acute social stress
Parkinson's disease (PD) risk is increased by stress and certain gene mutations, including the most prevalent PD-linked mutation -G2019S. Both PD and stress increase risk for psychiatric symptoms, yet it is unclear how PD-risk genes alter neural circuitry in response to stress that may promote...
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Published in: | Journal of neurophysiology 2020-06, Vol.123 (6), p.2382-2389 |
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creator | Guevara, Christopher A Matikainen-Ankney, Bridget A Kezunovic, Nebojsa LeClair, Katherine Conway, Alexander P Menard, Caroline Flanigan, Meghan E Pfau, Madeline Russo, Scott J Benson, Deanna L Huntley, George W |
description | Parkinson's disease (PD) risk is increased by stress and certain gene mutations, including the most prevalent PD-linked mutation
-G2019S. Both PD and stress increase risk for psychiatric symptoms, yet it is unclear how PD-risk genes alter neural circuitry in response to stress that may promote psychopathology. Here we show significant differences between adult G2019S knockin and wild-type (wt) mice in stress-induced behaviors, with an unexpected uncoupling of depression-like and hedonia-like responses in G2019S mice. Moreover, mutant spiny projection neurons in nucleus accumbens (NAc) lack an adaptive, stress-induced change in excitability displayed by wt neurons, and instead show stress-induced changes in synaptic properties that wt neurons lack. Some synaptic alterations in NAc are already evident early in postnatal life. Thus G2019S alters the magnitude and direction of behavioral responses to stress that may reflect unique modifications of adaptive plasticity in cells and circuits implicated in psychopathology in humans.
Depression is associated with Parkinson's disease (PD), and environmental stress is a risk factor for both. We investigated how LRRK2-G2019S PD mutation affects depression-like behaviors, synaptic function, and intrinsic neuronal excitability following stress. In response to stress, the mutation drives abnormal synaptic changes, prevents adaptive changes in intrinsic excitability, and leads to aberrant behaviors, thus defining new ways in which PD mutations derail adaptive plasticity in response to stress that may contribute to disease onset. |
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-G2019S. Both PD and stress increase risk for psychiatric symptoms, yet it is unclear how PD-risk genes alter neural circuitry in response to stress that may promote psychopathology. Here we show significant differences between adult G2019S knockin and wild-type (wt) mice in stress-induced behaviors, with an unexpected uncoupling of depression-like and hedonia-like responses in G2019S mice. Moreover, mutant spiny projection neurons in nucleus accumbens (NAc) lack an adaptive, stress-induced change in excitability displayed by wt neurons, and instead show stress-induced changes in synaptic properties that wt neurons lack. Some synaptic alterations in NAc are already evident early in postnatal life. Thus G2019S alters the magnitude and direction of behavioral responses to stress that may reflect unique modifications of adaptive plasticity in cells and circuits implicated in psychopathology in humans.
Depression is associated with Parkinson's disease (PD), and environmental stress is a risk factor for both. We investigated how LRRK2-G2019S PD mutation affects depression-like behaviors, synaptic function, and intrinsic neuronal excitability following stress. In response to stress, the mutation drives abnormal synaptic changes, prevents adaptive changes in intrinsic excitability, and leads to aberrant behaviors, thus defining new ways in which PD mutations derail adaptive plasticity in response to stress that may contribute to disease onset.</description><identifier>ISSN: 0022-3077</identifier><identifier>EISSN: 1522-1598</identifier><identifier>DOI: 10.1152/JN.00137.2020</identifier><identifier>PMID: 32374202</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Rapid Report</subject><ispartof>Journal of neurophysiology, 2020-06, Vol.123 (6), p.2382-2389</ispartof><rights>Copyright © 2020 the American Physiological Society 2020 American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-bd84083f1a601b60b5acd8bc1ccd98f11e5cd895e036d25c219ddee6a447b7c43</citedby><cites>FETCH-LOGICAL-c387t-bd84083f1a601b60b5acd8bc1ccd98f11e5cd895e036d25c219ddee6a447b7c43</cites><orcidid>0000-0002-3185-7459 ; 0000-0002-6470-1805 ; 0000-0001-6755-9317 ; 0000-0003-2075-7740 ; 0000-0003-3645-6192 ; 0000-0001-9217-2448 ; 0000-0001-8623-2002 ; 0000-0001-8202-7378 ; 0000-0001-7037-1147</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32374202$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guevara, Christopher A</creatorcontrib><creatorcontrib>Matikainen-Ankney, Bridget A</creatorcontrib><creatorcontrib>Kezunovic, Nebojsa</creatorcontrib><creatorcontrib>LeClair, Katherine</creatorcontrib><creatorcontrib>Conway, Alexander P</creatorcontrib><creatorcontrib>Menard, Caroline</creatorcontrib><creatorcontrib>Flanigan, Meghan E</creatorcontrib><creatorcontrib>Pfau, Madeline</creatorcontrib><creatorcontrib>Russo, Scott J</creatorcontrib><creatorcontrib>Benson, Deanna L</creatorcontrib><creatorcontrib>Huntley, George W</creatorcontrib><title>LRRK2 mutation alters behavioral, synaptic, and nonsynaptic adaptations to acute social stress</title><title>Journal of neurophysiology</title><addtitle>J Neurophysiol</addtitle><description>Parkinson's disease (PD) risk is increased by stress and certain gene mutations, including the most prevalent PD-linked mutation
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Depression is associated with Parkinson's disease (PD), and environmental stress is a risk factor for both. We investigated how LRRK2-G2019S PD mutation affects depression-like behaviors, synaptic function, and intrinsic neuronal excitability following stress. In response to stress, the mutation drives abnormal synaptic changes, prevents adaptive changes in intrinsic excitability, and leads to aberrant behaviors, thus defining new ways in which PD mutations derail adaptive plasticity in response to stress that may contribute to disease onset.</description><subject>Rapid Report</subject><issn>0022-3077</issn><issn>1522-1598</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNpVUctOwzAQtBCIlsKRK_KRQ1PWdlInFyRU8a5AquCK5dgOTZXaJXYq9e9Jn4LT7GNmdqVB6JLAgJCE3ry8DQAI4wMKFI5Qt53RiCRZeoy6AG3NgPMOOvN-BgA8AXqKOowyHreCLvoaTyavFM-bIEPpLJZVMLXHuZnKZelqWfWxX1m5CKXqY2k1ts7uB1jqFjc6j4PDUjXBYO9UKSvsQ228P0cnhay8udhhD30-3H-MnqLx--Pz6G4cKZbyEOU6jSFlBZFDIPkQ8kQqneaKKKWztCDEJG2fJQbYUNNEUZJpbcxQxjHPuYpZD91ufRdNPjdaGRva38WiLueyXgknS_F_Y8up-HZLwRkhnEFrcL0zqN1PY3wQ89IrU1XSGtd4QVmWURZvqdGWqmrnfW2KwxkCYp2JmFmxyUSsM2n5V39_O7D3IbBfVqeJow</recordid><startdate>20200601</startdate><enddate>20200601</enddate><creator>Guevara, Christopher A</creator><creator>Matikainen-Ankney, Bridget A</creator><creator>Kezunovic, Nebojsa</creator><creator>LeClair, Katherine</creator><creator>Conway, Alexander P</creator><creator>Menard, Caroline</creator><creator>Flanigan, Meghan E</creator><creator>Pfau, Madeline</creator><creator>Russo, Scott J</creator><creator>Benson, Deanna L</creator><creator>Huntley, George W</creator><general>American Physiological Society</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3185-7459</orcidid><orcidid>https://orcid.org/0000-0002-6470-1805</orcidid><orcidid>https://orcid.org/0000-0001-6755-9317</orcidid><orcidid>https://orcid.org/0000-0003-2075-7740</orcidid><orcidid>https://orcid.org/0000-0003-3645-6192</orcidid><orcidid>https://orcid.org/0000-0001-9217-2448</orcidid><orcidid>https://orcid.org/0000-0001-8623-2002</orcidid><orcidid>https://orcid.org/0000-0001-8202-7378</orcidid><orcidid>https://orcid.org/0000-0001-7037-1147</orcidid></search><sort><creationdate>20200601</creationdate><title>LRRK2 mutation alters behavioral, synaptic, and nonsynaptic adaptations to acute social stress</title><author>Guevara, Christopher A ; Matikainen-Ankney, Bridget A ; Kezunovic, Nebojsa ; LeClair, Katherine ; Conway, Alexander P ; Menard, Caroline ; Flanigan, Meghan E ; Pfau, Madeline ; Russo, Scott J ; Benson, Deanna L ; Huntley, George W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-bd84083f1a601b60b5acd8bc1ccd98f11e5cd895e036d25c219ddee6a447b7c43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Rapid Report</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guevara, Christopher A</creatorcontrib><creatorcontrib>Matikainen-Ankney, Bridget A</creatorcontrib><creatorcontrib>Kezunovic, Nebojsa</creatorcontrib><creatorcontrib>LeClair, Katherine</creatorcontrib><creatorcontrib>Conway, Alexander P</creatorcontrib><creatorcontrib>Menard, Caroline</creatorcontrib><creatorcontrib>Flanigan, Meghan E</creatorcontrib><creatorcontrib>Pfau, Madeline</creatorcontrib><creatorcontrib>Russo, Scott J</creatorcontrib><creatorcontrib>Benson, Deanna L</creatorcontrib><creatorcontrib>Huntley, George W</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of neurophysiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guevara, Christopher A</au><au>Matikainen-Ankney, Bridget A</au><au>Kezunovic, Nebojsa</au><au>LeClair, Katherine</au><au>Conway, Alexander P</au><au>Menard, Caroline</au><au>Flanigan, Meghan E</au><au>Pfau, Madeline</au><au>Russo, Scott J</au><au>Benson, Deanna L</au><au>Huntley, George W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>LRRK2 mutation alters behavioral, synaptic, and nonsynaptic adaptations to acute social stress</atitle><jtitle>Journal of neurophysiology</jtitle><addtitle>J Neurophysiol</addtitle><date>2020-06-01</date><risdate>2020</risdate><volume>123</volume><issue>6</issue><spage>2382</spage><epage>2389</epage><pages>2382-2389</pages><issn>0022-3077</issn><eissn>1522-1598</eissn><abstract>Parkinson's disease (PD) risk is increased by stress and certain gene mutations, including the most prevalent PD-linked mutation
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Depression is associated with Parkinson's disease (PD), and environmental stress is a risk factor for both. We investigated how LRRK2-G2019S PD mutation affects depression-like behaviors, synaptic function, and intrinsic neuronal excitability following stress. In response to stress, the mutation drives abnormal synaptic changes, prevents adaptive changes in intrinsic excitability, and leads to aberrant behaviors, thus defining new ways in which PD mutations derail adaptive plasticity in response to stress that may contribute to disease onset.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>32374202</pmid><doi>10.1152/JN.00137.2020</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-3185-7459</orcidid><orcidid>https://orcid.org/0000-0002-6470-1805</orcidid><orcidid>https://orcid.org/0000-0001-6755-9317</orcidid><orcidid>https://orcid.org/0000-0003-2075-7740</orcidid><orcidid>https://orcid.org/0000-0003-3645-6192</orcidid><orcidid>https://orcid.org/0000-0001-9217-2448</orcidid><orcidid>https://orcid.org/0000-0001-8623-2002</orcidid><orcidid>https://orcid.org/0000-0001-8202-7378</orcidid><orcidid>https://orcid.org/0000-0001-7037-1147</orcidid><oa>free_for_read</oa></addata></record> |
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title | LRRK2 mutation alters behavioral, synaptic, and nonsynaptic adaptations to acute social stress |
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