Presynaptic calcium channel inhibition underlies CB₁ cannabinoid receptor-mediated suppression of GABA release
CB1 cannabinoid receptors (CB1) are located at axon terminals and effectively control synaptic communication and thereby circuit operation widespread in the CNS. Although it is partially uncovered how CB1 activation leads to the reduction of synaptic excitation, the mechanisms of the decrease of GAB...
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Veröffentlicht in: | The Journal of neuroscience 2014-06, Vol.34 (23), p.7958-7963 |
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creator | Szabó, Gergely G Lenkey, Nora Holderith, Noemi Andrási, Tibor Nusser, Zoltan Hájos, Norbert |
description | CB1 cannabinoid receptors (CB1) are located at axon terminals and effectively control synaptic communication and thereby circuit operation widespread in the CNS. Although it is partially uncovered how CB1 activation leads to the reduction of synaptic excitation, the mechanisms of the decrease of GABA release upon activation of these cannabinoid receptors remain elusive. To determine the mechanisms underlying the suppression of synaptic transmission by CB1 at GABAergic synapses, we recorded unitary IPSCs (uIPSCs) at cholecystokinin-expressing interneuron-pyramidal cell connections and imaged presynaptic [Ca(2+)] transients in mouse hippocampal slices. Our results reveal a power function with an exponent of 2.2 between the amplitude of uIPSCs and intrabouton [Ca(2+)]. Altering CB1 function by either increasing endocannabinoid production or removing its tonic activity allowed us to demonstrate that CB1 controls GABA release by inhibiting Ca(2+) entry into presynaptic axon terminals via N-type (Cav2.2) Ca(2+) channels. These results provide evidence for modulation of intrabouton Ca(2+) influx into GABAergic axon terminals by CB1, leading to the effective suppression of synaptic inhibition. |
doi_str_mv | 10.1523/JNEUROSCI.0247-14.2014 |
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Although it is partially uncovered how CB1 activation leads to the reduction of synaptic excitation, the mechanisms of the decrease of GABA release upon activation of these cannabinoid receptors remain elusive. To determine the mechanisms underlying the suppression of synaptic transmission by CB1 at GABAergic synapses, we recorded unitary IPSCs (uIPSCs) at cholecystokinin-expressing interneuron-pyramidal cell connections and imaged presynaptic [Ca(2+)] transients in mouse hippocampal slices. Our results reveal a power function with an exponent of 2.2 between the amplitude of uIPSCs and intrabouton [Ca(2+)]. Altering CB1 function by either increasing endocannabinoid production or removing its tonic activity allowed us to demonstrate that CB1 controls GABA release by inhibiting Ca(2+) entry into presynaptic axon terminals via N-type (Cav2.2) Ca(2+) channels. These results provide evidence for modulation of intrabouton Ca(2+) influx into GABAergic axon terminals by CB1, leading to the effective suppression of synaptic inhibition.</description><identifier>ISSN: 0270-6474</identifier><identifier>ISSN: 1529-2401</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.0247-14.2014</identifier><identifier>PMID: 24899717</identifier><language>eng</language><publisher>United States: Society for Neuroscience</publisher><subject>Animals ; Animals, Newborn ; Brief Communications ; Calcium - metabolism ; Calcium Channel Blockers - pharmacology ; Cholecystokinin - genetics ; Cholecystokinin - pharmacology ; Female ; gamma-Aminobutyric Acid - metabolism ; Hippocampus - cytology ; In Vitro Techniques ; Inhibitory Postsynaptic Potentials - drug effects ; Inhibitory Postsynaptic Potentials - physiology ; Interneurons - drug effects ; Interneurons - physiology ; Luminescent Proteins - genetics ; Male ; Mice ; Mice, Transgenic ; omega-Conotoxin GVIA - pharmacology ; Piperidines - pharmacology ; Presynaptic Terminals - drug effects ; Presynaptic Terminals - metabolism ; Pyrazoles - pharmacology ; Receptor, Cannabinoid, CB1 - metabolism ; Synapses - drug effects ; Synapses - physiology</subject><ispartof>The Journal of neuroscience, 2014-06, Vol.34 (23), p.7958-7963</ispartof><rights>Copyright © 2014 the authors 0270-6474/14/347958-06$15.00/0.</rights><rights>Copyright © 2014 the authors 0270-6474/14/347958-06$15.00/0 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c513t-c834be39b772ca005c9f4b7b50ee87661b5bf2580fad5c2529d3309bd3d022683</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608264/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608264/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24899717$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Szabó, Gergely G</creatorcontrib><creatorcontrib>Lenkey, Nora</creatorcontrib><creatorcontrib>Holderith, Noemi</creatorcontrib><creatorcontrib>Andrási, Tibor</creatorcontrib><creatorcontrib>Nusser, Zoltan</creatorcontrib><creatorcontrib>Hájos, Norbert</creatorcontrib><title>Presynaptic calcium channel inhibition underlies CB₁ cannabinoid receptor-mediated suppression of GABA release</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>CB1 cannabinoid receptors (CB1) are located at axon terminals and effectively control synaptic communication and thereby circuit operation widespread in the CNS. Although it is partially uncovered how CB1 activation leads to the reduction of synaptic excitation, the mechanisms of the decrease of GABA release upon activation of these cannabinoid receptors remain elusive. To determine the mechanisms underlying the suppression of synaptic transmission by CB1 at GABAergic synapses, we recorded unitary IPSCs (uIPSCs) at cholecystokinin-expressing interneuron-pyramidal cell connections and imaged presynaptic [Ca(2+)] transients in mouse hippocampal slices. Our results reveal a power function with an exponent of 2.2 between the amplitude of uIPSCs and intrabouton [Ca(2+)]. Altering CB1 function by either increasing endocannabinoid production or removing its tonic activity allowed us to demonstrate that CB1 controls GABA release by inhibiting Ca(2+) entry into presynaptic axon terminals via N-type (Cav2.2) Ca(2+) channels. These results provide evidence for modulation of intrabouton Ca(2+) influx into GABAergic axon terminals by CB1, leading to the effective suppression of synaptic inhibition.</description><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Brief Communications</subject><subject>Calcium - metabolism</subject><subject>Calcium Channel Blockers - pharmacology</subject><subject>Cholecystokinin - genetics</subject><subject>Cholecystokinin - pharmacology</subject><subject>Female</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>Hippocampus - cytology</subject><subject>In Vitro Techniques</subject><subject>Inhibitory Postsynaptic Potentials - drug effects</subject><subject>Inhibitory Postsynaptic Potentials - physiology</subject><subject>Interneurons - drug effects</subject><subject>Interneurons - physiology</subject><subject>Luminescent Proteins - genetics</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>omega-Conotoxin GVIA - pharmacology</subject><subject>Piperidines - pharmacology</subject><subject>Presynaptic Terminals - drug effects</subject><subject>Presynaptic Terminals - metabolism</subject><subject>Pyrazoles - pharmacology</subject><subject>Receptor, Cannabinoid, CB1 - metabolism</subject><subject>Synapses - drug effects</subject><subject>Synapses - physiology</subject><issn>0270-6474</issn><issn>1529-2401</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1u1DAQxy1ERZfCK1Q5csky_oidXJC2q1KKKloVerZsZ8IaZe1gJ5V6hEflSUjUsqKnOfw_ZkY_Qk4prGnF-PvPX87vbq-_bi_XwIQqqVgzoOIFWc1qUzIB9CVZAVNQSqHEMXmd8w8AUEDVK3LMRN00iqoVGW4S5odghtG7wpne-WlfuJ0JAfvCh523fvQxFFNoMfUec7E9-_P712wNwVgfom-LhA6HMaZyj603I7ZFnoZh7s1LMnbFxeZsM7t6NBnfkKPO9BnfPs0Tcvfx_Nv2U3l1fXG53VyVrqJ8LF3NhUXeWKWYMwCVazphla0AsVZSUlvZjlU1dKatHJufbjmHxra8BcZkzU_Ih8feYbLzXQ7DmEyvh-T3Jj3oaLx-rgS_09_jvZYSaibFXPDuqSDFnxPmUe99dtj3JmCcsqZVRSVVUiy75KPVpZhzwu6whoJecOkDLr3g0lToBdccPP3_yEPsHx_-F6MWlaY</recordid><startdate>20140604</startdate><enddate>20140604</enddate><creator>Szabó, Gergely G</creator><creator>Lenkey, Nora</creator><creator>Holderith, Noemi</creator><creator>Andrási, Tibor</creator><creator>Nusser, Zoltan</creator><creator>Hájos, Norbert</creator><general>Society for Neuroscience</general><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>7TK</scope><scope>5PM</scope></search><sort><creationdate>20140604</creationdate><title>Presynaptic calcium channel inhibition underlies CB₁ cannabinoid receptor-mediated suppression of GABA release</title><author>Szabó, Gergely G ; Lenkey, Nora ; Holderith, Noemi ; Andrási, Tibor ; Nusser, Zoltan ; Hájos, Norbert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c513t-c834be39b772ca005c9f4b7b50ee87661b5bf2580fad5c2529d3309bd3d022683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Brief Communications</topic><topic>Calcium - metabolism</topic><topic>Calcium Channel Blockers - pharmacology</topic><topic>Cholecystokinin - genetics</topic><topic>Cholecystokinin - pharmacology</topic><topic>Female</topic><topic>gamma-Aminobutyric Acid - metabolism</topic><topic>Hippocampus - cytology</topic><topic>In Vitro Techniques</topic><topic>Inhibitory Postsynaptic Potentials - drug effects</topic><topic>Inhibitory Postsynaptic Potentials - physiology</topic><topic>Interneurons - drug effects</topic><topic>Interneurons - physiology</topic><topic>Luminescent Proteins - genetics</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>omega-Conotoxin GVIA - pharmacology</topic><topic>Piperidines - pharmacology</topic><topic>Presynaptic Terminals - drug effects</topic><topic>Presynaptic Terminals - metabolism</topic><topic>Pyrazoles - pharmacology</topic><topic>Receptor, Cannabinoid, CB1 - metabolism</topic><topic>Synapses - drug effects</topic><topic>Synapses - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Szabó, Gergely G</creatorcontrib><creatorcontrib>Lenkey, Nora</creatorcontrib><creatorcontrib>Holderith, Noemi</creatorcontrib><creatorcontrib>Andrási, Tibor</creatorcontrib><creatorcontrib>Nusser, Zoltan</creatorcontrib><creatorcontrib>Hájos, Norbert</creatorcontrib><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>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Szabó, Gergely G</au><au>Lenkey, Nora</au><au>Holderith, Noemi</au><au>Andrási, Tibor</au><au>Nusser, Zoltan</au><au>Hájos, Norbert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Presynaptic calcium channel inhibition underlies CB₁ cannabinoid receptor-mediated suppression of GABA release</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2014-06-04</date><risdate>2014</risdate><volume>34</volume><issue>23</issue><spage>7958</spage><epage>7963</epage><pages>7958-7963</pages><issn>0270-6474</issn><issn>1529-2401</issn><eissn>1529-2401</eissn><abstract>CB1 cannabinoid receptors (CB1) are located at axon terminals and effectively control synaptic communication and thereby circuit operation widespread in the CNS. Although it is partially uncovered how CB1 activation leads to the reduction of synaptic excitation, the mechanisms of the decrease of GABA release upon activation of these cannabinoid receptors remain elusive. To determine the mechanisms underlying the suppression of synaptic transmission by CB1 at GABAergic synapses, we recorded unitary IPSCs (uIPSCs) at cholecystokinin-expressing interneuron-pyramidal cell connections and imaged presynaptic [Ca(2+)] transients in mouse hippocampal slices. Our results reveal a power function with an exponent of 2.2 between the amplitude of uIPSCs and intrabouton [Ca(2+)]. Altering CB1 function by either increasing endocannabinoid production or removing its tonic activity allowed us to demonstrate that CB1 controls GABA release by inhibiting Ca(2+) entry into presynaptic axon terminals via N-type (Cav2.2) Ca(2+) channels. 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subjects | Animals Animals, Newborn Brief Communications Calcium - metabolism Calcium Channel Blockers - pharmacology Cholecystokinin - genetics Cholecystokinin - pharmacology Female gamma-Aminobutyric Acid - metabolism Hippocampus - cytology In Vitro Techniques Inhibitory Postsynaptic Potentials - drug effects Inhibitory Postsynaptic Potentials - physiology Interneurons - drug effects Interneurons - physiology Luminescent Proteins - genetics Male Mice Mice, Transgenic omega-Conotoxin GVIA - pharmacology Piperidines - pharmacology Presynaptic Terminals - drug effects Presynaptic Terminals - metabolism Pyrazoles - pharmacology Receptor, Cannabinoid, CB1 - metabolism Synapses - drug effects Synapses - physiology |
title | Presynaptic calcium channel inhibition underlies CB₁ cannabinoid receptor-mediated suppression of GABA release |
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