Manipulation of α4βδ GABAA receptors alters synaptic pruning in layer 3 prelimbic prefrontal cortex and impairs temporal order recognition: Implications for schizophrenia and autism

•α4βδ GABAA receptors increase at puberty in layer 3 male prelimbic cortex.•Targeting these receptors with drugs or by knock-out alters spine pruning.•α4 knock-out increases spines and impairs temporal order memory.•An α4βδ agonist decreases spines and impairs temporal order memory.•These findings m...

Full description

Saved in:
Bibliographic Details
Published in:Brain research 2024-07, Vol.1835, p.148929-148929, Article 148929
Main Authors: Smith, Sheryl S, Benanni, Safae, Jones, Quiana, Kenney, Lindsay, Evrard, Matthew R.
Format: Article
Language:English
Subjects:
Alpha4-beta-delta GABAA receptor
Autism spectrum disorder
Dendritic spine
Prelimbic prefrontal cortex
Schizophrenia
Temporal order memory
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by
cites cdi_FETCH-LOGICAL-c340t-55356c0e13dcaece18138498e608273d07a3fd9a9f7955d77563bf306d539c533
container_end_page 148929
container_issue
container_start_page 148929
container_title Brain research
container_volume 1835
creator Smith, Sheryl S
Benanni, Safae
Jones, Quiana
Kenney, Lindsay
Evrard, Matthew R.
description •α4βδ GABAA receptors increase at puberty in layer 3 male prelimbic cortex.•Targeting these receptors with drugs or by knock-out alters spine pruning.•α4 knock-out increases spines and impairs temporal order memory.•An α4βδ agonist decreases spines and impairs temporal order memory.•These findings may be relevant for ASD and SCZ where spine density/recency memory are abnormal. Temporal order memory is impaired in autism spectrum disorder (ASD) and schizophrenia (SCZ). These disorders, more prevalent in males, result in abnormal dendritic spine pruning during adolescence in layer 3 (L3) medial prefrontal cortex (mPFC), yielding either too many (ASD) or too few (SCZ) spines. Here we tested whether altering spine density in neural circuits including the mPFC could be associated with impaired temporal order memory in male mice. We have shown that α4βδ GABAA receptors (GABARs) emerge at puberty on spines of L5 prelimbic mPFC (PL) where they trigger pruning. We show here that α4βδ receptors also increase at puberty in L3 PL (P 
doi_str_mv 10.1016/j.brainres.2024.148929
format article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3037398552</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0006899324001835</els_id><sourcerecordid>3037398552</sourcerecordid><originalsourceid>FETCH-LOGICAL-c340t-55356c0e13dcaece18138498e608273d07a3fd9a9f7955d77563bf306d539c533</originalsourceid><addsrcrecordid>eNqFUU2P0zAQtRBIlIW_gHzkkuLEcRJzoqxgd6VFXOBsufZkd6rENraDKP8KxGF_RX8TbgtnTqOZN-_NxyPkZc3WNau717v1Nmp0EdK6YU27rttBNvIRWdVD31Rd07LHZMUY66pBSv6UPEtpV1LOJVuRh4_aYVgmndE76kd6-Nkefh1-06vNu82GRjAQso-J6ilDCWnvdMhoaIiLQ3dH0dFJ7yFSXkow4bw9gTBG77KeqPExw3eqnaU4B41FI8McfCyYj7YQywx_5_C4wBt6M4cJzWmbREcfaTL3-MOH-wgO9UlGLxnT_Jw8GfWU4MXfeEG-fHj_-fK6uv10dXO5ua0Mb1muhOCiMwxqbo0ux9RDzYdWDtCxoem5Zb3mo5Vajr0Uwva96Ph25KyzgksjOL8gr866IfqvC6SsZkwGpkk78EtSnPGey0GIprR251YTfUrlBSpEnHXcq5qpo1Vqp_5ZpY5WqbNVhfj2TIRyyDeEqJJBcAYsludkZT3-T-IPPC-m-w</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3037398552</pqid></control><display><type>article</type><title>Manipulation of α4βδ GABAA receptors alters synaptic pruning in layer 3 prelimbic prefrontal cortex and impairs temporal order recognition: Implications for schizophrenia and autism</title><source>Elsevier</source><creator>Smith, Sheryl S ; Benanni, Safae ; Jones, Quiana ; Kenney, Lindsay ; Evrard, Matthew R.</creator><creatorcontrib>Smith, Sheryl S ; Benanni, Safae ; Jones, Quiana ; Kenney, Lindsay ; Evrard, Matthew R.</creatorcontrib><description>•α4βδ GABAA receptors increase at puberty in layer 3 male prelimbic cortex.•Targeting these receptors with drugs or by knock-out alters spine pruning.•α4 knock-out increases spines and impairs temporal order memory.•An α4βδ agonist decreases spines and impairs temporal order memory.•These findings may be relevant for ASD and SCZ where spine density/recency memory are abnormal. Temporal order memory is impaired in autism spectrum disorder (ASD) and schizophrenia (SCZ). These disorders, more prevalent in males, result in abnormal dendritic spine pruning during adolescence in layer 3 (L3) medial prefrontal cortex (mPFC), yielding either too many (ASD) or too few (SCZ) spines. Here we tested whether altering spine density in neural circuits including the mPFC could be associated with impaired temporal order memory in male mice. We have shown that α4βδ GABAA receptors (GABARs) emerge at puberty on spines of L5 prelimbic mPFC (PL) where they trigger pruning. We show here that α4βδ receptors also increase at puberty in L3 PL (P &lt; 0.0001) and used these receptors as a target to manipulate spine density here. Pubertal injection (14 d) of the GABA agonist gaboxadol, at a dose (3 mg/kg) selective for α4βδ, reduced L3 spine density by half (P &lt; 0.0001), while α4 knock-out increased spine density ∼ 40 % (P &lt; 0.0001), mimicking spine densities in SCZ and ASD, respectively. In both cases, performance on the mPFC-dependent temporal order recognition task was impaired, resulting in decreases in the discrimination ratio which assesses preference for the novel object: −0.39 ± 0.15, gaboxadol versus 0.52 ± 0.09, vehicle; P = 0.0002; −0.048 ± 0.10, α4 KO versus 0.49 ± 0.04, wild-type; P &lt; 0.0001. In contrast, the number of approaches was unaltered, reflecting unchanged locomotion. These data suggest that altering α4βδ GABAR expression/activity alters spine density in L3 mPFC and impairs temporal order memory to mimic changes in ASD and SCZ. These findings may provide insight into these disorders.</description><identifier>ISSN: 0006-8993</identifier><identifier>EISSN: 1872-6240</identifier><identifier>DOI: 10.1016/j.brainres.2024.148929</identifier><language>eng</language><publisher>Elsevier B.V</publisher><subject>Alpha4-beta-delta GABAA receptor ; Autism spectrum disorder ; Dendritic spine ; Prelimbic prefrontal cortex ; Schizophrenia ; Temporal order memory</subject><ispartof>Brain research, 2024-07, Vol.1835, p.148929-148929, Article 148929</ispartof><rights>2024 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c340t-55356c0e13dcaece18138498e608273d07a3fd9a9f7955d77563bf306d539c533</cites><orcidid>0000-0003-4308-3267 ; 0000-0003-4283-1972</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids></links><search><creatorcontrib>Smith, Sheryl S</creatorcontrib><creatorcontrib>Benanni, Safae</creatorcontrib><creatorcontrib>Jones, Quiana</creatorcontrib><creatorcontrib>Kenney, Lindsay</creatorcontrib><creatorcontrib>Evrard, Matthew R.</creatorcontrib><title>Manipulation of α4βδ GABAA receptors alters synaptic pruning in layer 3 prelimbic prefrontal cortex and impairs temporal order recognition: Implications for schizophrenia and autism</title><title>Brain research</title><description>•α4βδ GABAA receptors increase at puberty in layer 3 male prelimbic cortex.•Targeting these receptors with drugs or by knock-out alters spine pruning.•α4 knock-out increases spines and impairs temporal order memory.•An α4βδ agonist decreases spines and impairs temporal order memory.•These findings may be relevant for ASD and SCZ where spine density/recency memory are abnormal. Temporal order memory is impaired in autism spectrum disorder (ASD) and schizophrenia (SCZ). These disorders, more prevalent in males, result in abnormal dendritic spine pruning during adolescence in layer 3 (L3) medial prefrontal cortex (mPFC), yielding either too many (ASD) or too few (SCZ) spines. Here we tested whether altering spine density in neural circuits including the mPFC could be associated with impaired temporal order memory in male mice. We have shown that α4βδ GABAA receptors (GABARs) emerge at puberty on spines of L5 prelimbic mPFC (PL) where they trigger pruning. We show here that α4βδ receptors also increase at puberty in L3 PL (P &lt; 0.0001) and used these receptors as a target to manipulate spine density here. Pubertal injection (14 d) of the GABA agonist gaboxadol, at a dose (3 mg/kg) selective for α4βδ, reduced L3 spine density by half (P &lt; 0.0001), while α4 knock-out increased spine density ∼ 40 % (P &lt; 0.0001), mimicking spine densities in SCZ and ASD, respectively. In both cases, performance on the mPFC-dependent temporal order recognition task was impaired, resulting in decreases in the discrimination ratio which assesses preference for the novel object: −0.39 ± 0.15, gaboxadol versus 0.52 ± 0.09, vehicle; P = 0.0002; −0.048 ± 0.10, α4 KO versus 0.49 ± 0.04, wild-type; P &lt; 0.0001. In contrast, the number of approaches was unaltered, reflecting unchanged locomotion. These data suggest that altering α4βδ GABAR expression/activity alters spine density in L3 mPFC and impairs temporal order memory to mimic changes in ASD and SCZ. These findings may provide insight into these disorders.</description><subject>Alpha4-beta-delta GABAA receptor</subject><subject>Autism spectrum disorder</subject><subject>Dendritic spine</subject><subject>Prelimbic prefrontal cortex</subject><subject>Schizophrenia</subject><subject>Temporal order memory</subject><issn>0006-8993</issn><issn>1872-6240</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNqFUU2P0zAQtRBIlIW_gHzkkuLEcRJzoqxgd6VFXOBsufZkd6rENraDKP8KxGF_RX8TbgtnTqOZN-_NxyPkZc3WNau717v1Nmp0EdK6YU27rttBNvIRWdVD31Rd07LHZMUY66pBSv6UPEtpV1LOJVuRh4_aYVgmndE76kd6-Nkefh1-06vNu82GRjAQso-J6ilDCWnvdMhoaIiLQ3dH0dFJ7yFSXkow4bw9gTBG77KeqPExw3eqnaU4B41FI8McfCyYj7YQywx_5_C4wBt6M4cJzWmbREcfaTL3-MOH-wgO9UlGLxnT_Jw8GfWU4MXfeEG-fHj_-fK6uv10dXO5ua0Mb1muhOCiMwxqbo0ux9RDzYdWDtCxoem5Zb3mo5Vajr0Uwva96Ph25KyzgksjOL8gr866IfqvC6SsZkwGpkk78EtSnPGey0GIprR251YTfUrlBSpEnHXcq5qpo1Vqp_5ZpY5WqbNVhfj2TIRyyDeEqJJBcAYsludkZT3-T-IPPC-m-w</recordid><startdate>20240715</startdate><enddate>20240715</enddate><creator>Smith, Sheryl S</creator><creator>Benanni, Safae</creator><creator>Jones, Quiana</creator><creator>Kenney, Lindsay</creator><creator>Evrard, Matthew R.</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4308-3267</orcidid><orcidid>https://orcid.org/0000-0003-4283-1972</orcidid></search><sort><creationdate>20240715</creationdate><title>Manipulation of α4βδ GABAA receptors alters synaptic pruning in layer 3 prelimbic prefrontal cortex and impairs temporal order recognition: Implications for schizophrenia and autism</title><author>Smith, Sheryl S ; Benanni, Safae ; Jones, Quiana ; Kenney, Lindsay ; Evrard, Matthew R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c340t-55356c0e13dcaece18138498e608273d07a3fd9a9f7955d77563bf306d539c533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Alpha4-beta-delta GABAA receptor</topic><topic>Autism spectrum disorder</topic><topic>Dendritic spine</topic><topic>Prelimbic prefrontal cortex</topic><topic>Schizophrenia</topic><topic>Temporal order memory</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Smith, Sheryl S</creatorcontrib><creatorcontrib>Benanni, Safae</creatorcontrib><creatorcontrib>Jones, Quiana</creatorcontrib><creatorcontrib>Kenney, Lindsay</creatorcontrib><creatorcontrib>Evrard, Matthew R.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Brain research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Smith, Sheryl S</au><au>Benanni, Safae</au><au>Jones, Quiana</au><au>Kenney, Lindsay</au><au>Evrard, Matthew R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Manipulation of α4βδ GABAA receptors alters synaptic pruning in layer 3 prelimbic prefrontal cortex and impairs temporal order recognition: Implications for schizophrenia and autism</atitle><jtitle>Brain research</jtitle><date>2024-07-15</date><risdate>2024</risdate><volume>1835</volume><spage>148929</spage><epage>148929</epage><pages>148929-148929</pages><artnum>148929</artnum><issn>0006-8993</issn><eissn>1872-6240</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>•α4βδ GABAA receptors increase at puberty in layer 3 male prelimbic cortex.•Targeting these receptors with drugs or by knock-out alters spine pruning.•α4 knock-out increases spines and impairs temporal order memory.•An α4βδ agonist decreases spines and impairs temporal order memory.•These findings may be relevant for ASD and SCZ where spine density/recency memory are abnormal. Temporal order memory is impaired in autism spectrum disorder (ASD) and schizophrenia (SCZ). These disorders, more prevalent in males, result in abnormal dendritic spine pruning during adolescence in layer 3 (L3) medial prefrontal cortex (mPFC), yielding either too many (ASD) or too few (SCZ) spines. Here we tested whether altering spine density in neural circuits including the mPFC could be associated with impaired temporal order memory in male mice. We have shown that α4βδ GABAA receptors (GABARs) emerge at puberty on spines of L5 prelimbic mPFC (PL) where they trigger pruning. We show here that α4βδ receptors also increase at puberty in L3 PL (P &lt; 0.0001) and used these receptors as a target to manipulate spine density here. Pubertal injection (14 d) of the GABA agonist gaboxadol, at a dose (3 mg/kg) selective for α4βδ, reduced L3 spine density by half (P &lt; 0.0001), while α4 knock-out increased spine density ∼ 40 % (P &lt; 0.0001), mimicking spine densities in SCZ and ASD, respectively. In both cases, performance on the mPFC-dependent temporal order recognition task was impaired, resulting in decreases in the discrimination ratio which assesses preference for the novel object: −0.39 ± 0.15, gaboxadol versus 0.52 ± 0.09, vehicle; P = 0.0002; −0.048 ± 0.10, α4 KO versus 0.49 ± 0.04, wild-type; P &lt; 0.0001. In contrast, the number of approaches was unaltered, reflecting unchanged locomotion. These data suggest that altering α4βδ GABAR expression/activity alters spine density in L3 mPFC and impairs temporal order memory to mimic changes in ASD and SCZ. These findings may provide insight into these disorders.</abstract><pub>Elsevier B.V</pub><doi>10.1016/j.brainres.2024.148929</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0003-4308-3267</orcidid><orcidid>https://orcid.org/0000-0003-4283-1972</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0006-8993
ispartof Brain research, 2024-07, Vol.1835, p.148929-148929, Article 148929
issn 0006-8993
1872-6240
language eng
recordid cdi_proquest_miscellaneous_3037398552
source Elsevier
subjects Alpha4-beta-delta GABAA receptor
Autism spectrum disorder
Dendritic spine
Prelimbic prefrontal cortex
Schizophrenia
Temporal order memory
title Manipulation of α4βδ GABAA receptors alters synaptic pruning in layer 3 prelimbic prefrontal cortex and impairs temporal order recognition: Implications for schizophrenia and autism
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-22T16%3A22%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Manipulation%20of%20%CE%B14%CE%B2%CE%B4%20GABAA%20receptors%20alters%20synaptic%20pruning%20in%20layer%203%20prelimbic%20prefrontal%20cortex%20and%20impairs%20temporal%20order%20recognition:%20Implications%20for%20schizophrenia%20and%20autism&rft.jtitle=Brain%20research&rft.au=Smith,%20Sheryl%20S&rft.date=2024-07-15&rft.volume=1835&rft.spage=148929&rft.epage=148929&rft.pages=148929-148929&rft.artnum=148929&rft.issn=0006-8993&rft.eissn=1872-6240&rft_id=info:doi/10.1016/j.brainres.2024.148929&rft_dat=%3Cproquest_cross%3E3037398552%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c340t-55356c0e13dcaece18138498e608273d07a3fd9a9f7955d77563bf306d539c533%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=3037398552&rft_id=info:pmid/&rfr_iscdi=true