Excitation-Transcription Coupling in Parvalbumin-Positive Interneurons Employs a Novel CaM Kinase-Dependent Pathway Distinct from Excitatory Neurons
Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity, and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is po...
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creator | Cohen, Samuel M. Ma, Huan Kuchibhotla, Kishore V. Watson, Brendon O. Buzsáki, György Froemke, Robert C. Tsien, Richard W. |
description | Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity, and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. We report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca2+ influx through CaV1 channels triggers CaM nuclear translocation via local Ca2+ signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca2+ transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and they are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease.
•Voltage-gated Ca2+ influx triggers nuclear translocation of CaM in PV+ interneurons•CaMK signaling promotes CREB phosphorylation and activates key genes in PV+ cells•γCaMKI, not γCaMKII, operates to shuttle CaM to the nucleus in PV+ cells•Low CaMKIV levels rate-limit CREB phosphorylation in PV+ cells
Activity-dependent gene regulation is critical for long-term plasticity. Cohen et al. demonstrate that PV+ cortical interneurons rely on a CaM kinase-dependent signaling pathway, hinging on γCaMKI and rate-limited by CaMKIV, to trigger CREB phosphorylation and gene expression. |
doi_str_mv | 10.1016/j.neuron.2016.03.001 |
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•Voltage-gated Ca2+ influx triggers nuclear translocation of CaM in PV+ interneurons•CaMK signaling promotes CREB phosphorylation and activates key genes in PV+ cells•γCaMKI, not γCaMKII, operates to shuttle CaM to the nucleus in PV+ cells•Low CaMKIV levels rate-limit CREB phosphorylation in PV+ cells
Activity-dependent gene regulation is critical for long-term plasticity. Cohen et al. demonstrate that PV+ cortical interneurons rely on a CaM kinase-dependent signaling pathway, hinging on γCaMKI and rate-limited by CaMKIV, to trigger CREB phosphorylation and gene expression.</description><identifier>ISSN: 0896-6273</identifier><identifier>EISSN: 1097-4199</identifier><identifier>DOI: 10.1016/j.neuron.2016.03.001</identifier><identifier>PMID: 27041500</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acoustic Stimulation ; Animals ; Auditory Cortex - metabolism ; Calcium - metabolism ; Calcium-Calmodulin-Dependent Protein Kinases - metabolism ; Caveolin 1 - physiology ; Cyclic AMP Response Element-Binding Protein - metabolism ; Experiments ; Gene expression ; Immunoglobulins ; Interneurons - metabolism ; Interneurons - physiology ; Isoenzymes - metabolism ; Kinases ; Mice ; Neurons ; Neurons - metabolism ; Neurons - physiology ; Parvalbumins - metabolism ; Phosphorylation ; Rats ; Signal Transduction ; Statistical analysis ; Transcription, Genetic - physiology</subject><ispartof>Neuron (Cambridge, Mass.), 2016-04, Vol.90 (2), p.292-307</ispartof><rights>2016 Elsevier Inc.</rights><rights>Copyright © 2016 Elsevier Inc. All rights reserved.</rights><rights>Copyright Elsevier Limited Apr 20, 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c590t-130f4e2ae26e4575f2fdd3585dd0f01df0531625c1017db18fa842dc580a7d633</citedby><cites>FETCH-LOGICAL-c590t-130f4e2ae26e4575f2fdd3585dd0f01df0531625c1017db18fa842dc580a7d633</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S089662731600180X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27041500$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cohen, Samuel M.</creatorcontrib><creatorcontrib>Ma, Huan</creatorcontrib><creatorcontrib>Kuchibhotla, Kishore V.</creatorcontrib><creatorcontrib>Watson, Brendon O.</creatorcontrib><creatorcontrib>Buzsáki, György</creatorcontrib><creatorcontrib>Froemke, Robert C.</creatorcontrib><creatorcontrib>Tsien, Richard W.</creatorcontrib><title>Excitation-Transcription Coupling in Parvalbumin-Positive Interneurons Employs a Novel CaM Kinase-Dependent Pathway Distinct from Excitatory Neurons</title><title>Neuron (Cambridge, Mass.)</title><addtitle>Neuron</addtitle><description>Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity, and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. We report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca2+ influx through CaV1 channels triggers CaM nuclear translocation via local Ca2+ signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca2+ transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and they are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease.
•Voltage-gated Ca2+ influx triggers nuclear translocation of CaM in PV+ interneurons•CaMK signaling promotes CREB phosphorylation and activates key genes in PV+ cells•γCaMKI, not γCaMKII, operates to shuttle CaM to the nucleus in PV+ cells•Low CaMKIV levels rate-limit CREB phosphorylation in PV+ cells
Activity-dependent gene regulation is critical for long-term plasticity. Cohen et al. demonstrate that PV+ cortical interneurons rely on a CaM kinase-dependent signaling pathway, hinging on γCaMKI and rate-limited by CaMKIV, to trigger CREB phosphorylation and gene expression.</description><subject>Acoustic Stimulation</subject><subject>Animals</subject><subject>Auditory Cortex - metabolism</subject><subject>Calcium - metabolism</subject><subject>Calcium-Calmodulin-Dependent Protein Kinases - metabolism</subject><subject>Caveolin 1 - physiology</subject><subject>Cyclic AMP Response Element-Binding Protein - metabolism</subject><subject>Experiments</subject><subject>Gene expression</subject><subject>Immunoglobulins</subject><subject>Interneurons - metabolism</subject><subject>Interneurons - physiology</subject><subject>Isoenzymes - metabolism</subject><subject>Kinases</subject><subject>Mice</subject><subject>Neurons</subject><subject>Neurons - metabolism</subject><subject>Neurons - physiology</subject><subject>Parvalbumins - metabolism</subject><subject>Phosphorylation</subject><subject>Rats</subject><subject>Signal Transduction</subject><subject>Statistical analysis</subject><subject>Transcription, Genetic - physiology</subject><issn>0896-6273</issn><issn>1097-4199</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNks1u1DAUhSMEokPhDRCyxKabBNuJ42SDhKYDVJTSRVlbHvum9Sixg-0E5j14YDzKUH4WCG-sK3_3-Pj4ZtlzgguCSf1qV1iYvLMFTVWBywJj8iBbEdzyvCJt-zBb4aat85ry8iR7EsIuARVryePshHJcEYbxKvu--aZMlNE4m994aYPyZjxUaO2msTf2FhmLrqWfZb-dBmPzaxdMNDOgCxvBLx4C2gxj7_YBSXTlZujRWn5EH4yVAfJzGMFqsDHJxLuvco_OTYjGqog67wZ0dOD8Hl0tak-zR53sAzw77qfZ57ebm_X7_PLTu4v1m8tcsRbHnJS4q4BKoDVUjLOOdlqXrGFa4w4T3WFWkpoylfLiekuaTjYV1Yo1WHJdl-Vp9nrRHaftAFolj172YvRmkH4vnDTizxNr7sStm0XV1HXDSRI4Owp492WCEMVggoK-lxbcFAThDW95WvR_0LKluG1ZQl_-he7c5G1K4kAxRnnTVImqFkp5F4KH7t43weIwIWInlt8RhwkRuBRpAFLbi9_ffN_0cyR-hQIp-dmAF0EZsAq08aCi0M78-4YfcDjSNw</recordid><startdate>20160420</startdate><enddate>20160420</enddate><creator>Cohen, Samuel M.</creator><creator>Ma, Huan</creator><creator>Kuchibhotla, Kishore V.</creator><creator>Watson, Brendon O.</creator><creator>Buzsáki, György</creator><creator>Froemke, Robert C.</creator><creator>Tsien, Richard W.</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160420</creationdate><title>Excitation-Transcription Coupling in Parvalbumin-Positive Interneurons Employs a Novel CaM Kinase-Dependent Pathway Distinct from Excitatory Neurons</title><author>Cohen, Samuel M. ; Ma, Huan ; Kuchibhotla, Kishore V. ; Watson, Brendon O. ; Buzsáki, György ; Froemke, Robert C. ; Tsien, Richard W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c590t-130f4e2ae26e4575f2fdd3585dd0f01df0531625c1017db18fa842dc580a7d633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Acoustic Stimulation</topic><topic>Animals</topic><topic>Auditory Cortex - metabolism</topic><topic>Calcium - metabolism</topic><topic>Calcium-Calmodulin-Dependent Protein Kinases - metabolism</topic><topic>Caveolin 1 - physiology</topic><topic>Cyclic AMP Response Element-Binding Protein - metabolism</topic><topic>Experiments</topic><topic>Gene expression</topic><topic>Immunoglobulins</topic><topic>Interneurons - metabolism</topic><topic>Interneurons - physiology</topic><topic>Isoenzymes - metabolism</topic><topic>Kinases</topic><topic>Mice</topic><topic>Neurons</topic><topic>Neurons - metabolism</topic><topic>Neurons - physiology</topic><topic>Parvalbumins - metabolism</topic><topic>Phosphorylation</topic><topic>Rats</topic><topic>Signal Transduction</topic><topic>Statistical analysis</topic><topic>Transcription, Genetic - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cohen, Samuel M.</creatorcontrib><creatorcontrib>Ma, Huan</creatorcontrib><creatorcontrib>Kuchibhotla, Kishore V.</creatorcontrib><creatorcontrib>Watson, Brendon O.</creatorcontrib><creatorcontrib>Buzsáki, György</creatorcontrib><creatorcontrib>Froemke, Robert C.</creatorcontrib><creatorcontrib>Tsien, Richard W.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Neuron (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cohen, Samuel M.</au><au>Ma, Huan</au><au>Kuchibhotla, Kishore V.</au><au>Watson, Brendon O.</au><au>Buzsáki, György</au><au>Froemke, Robert C.</au><au>Tsien, Richard W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Excitation-Transcription Coupling in Parvalbumin-Positive Interneurons Employs a Novel CaM Kinase-Dependent Pathway Distinct from Excitatory Neurons</atitle><jtitle>Neuron (Cambridge, Mass.)</jtitle><addtitle>Neuron</addtitle><date>2016-04-20</date><risdate>2016</risdate><volume>90</volume><issue>2</issue><spage>292</spage><epage>307</epage><pages>292-307</pages><issn>0896-6273</issn><eissn>1097-4199</eissn><abstract>Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity, and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. We report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca2+ influx through CaV1 channels triggers CaM nuclear translocation via local Ca2+ signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca2+ transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and they are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease.
•Voltage-gated Ca2+ influx triggers nuclear translocation of CaM in PV+ interneurons•CaMK signaling promotes CREB phosphorylation and activates key genes in PV+ cells•γCaMKI, not γCaMKII, operates to shuttle CaM to the nucleus in PV+ cells•Low CaMKIV levels rate-limit CREB phosphorylation in PV+ cells
Activity-dependent gene regulation is critical for long-term plasticity. Cohen et al. demonstrate that PV+ cortical interneurons rely on a CaM kinase-dependent signaling pathway, hinging on γCaMKI and rate-limited by CaMKIV, to trigger CREB phosphorylation and gene expression.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27041500</pmid><doi>10.1016/j.neuron.2016.03.001</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Acoustic Stimulation Animals Auditory Cortex - metabolism Calcium - metabolism Calcium-Calmodulin-Dependent Protein Kinases - metabolism Caveolin 1 - physiology Cyclic AMP Response Element-Binding Protein - metabolism Experiments Gene expression Immunoglobulins Interneurons - metabolism Interneurons - physiology Isoenzymes - metabolism Kinases Mice Neurons Neurons - metabolism Neurons - physiology Parvalbumins - metabolism Phosphorylation Rats Signal Transduction Statistical analysis Transcription, Genetic - physiology |
title | Excitation-Transcription Coupling in Parvalbumin-Positive Interneurons Employs a Novel CaM Kinase-Dependent Pathway Distinct from Excitatory Neurons |
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