Abstract
Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB1 receptors (CB1Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABAA receptors (GABAARs), potentiating currents activated by micromolar concentrations of γ-aminobutyric acid (GABA). However, the impact of this direct interaction on GABAergic inhibition in central nervous system is unknown. Here we report that currents mediated by recombinant GABAARs activated by high (synaptic) concentrations of GABA as well as GABAergic inhibitory postsynaptic currents (IPSCs) at neocortical fast spiking (FS) interneuron to pyramidal neuron synapses are suppressed by exogenous and endogenous cannabinoids in a CB1R-independent manner. This IPSC suppression may account for disruption of inhibitory control of pyramidal neurons by FS interneurons. At FS interneuron to pyramidal neuron synapses, endocannabinoids induce synaptic low-pass filtering of GABAAR-mediated currents evoked by high-frequency stimulation. The CB1R-independent suppression of inhibition is synapse specific. It does not occur in CB1R containing hippocampal cholecystokinin-positive interneuron to pyramidal neuron synapses. Furthermore, in contrast to synaptic receptors, the activity of extrasynaptic GABAARs in neocortical pyramidal neurons is enhanced by cannabinoids in a CB1R-independent manner. Thus, cannabinoids directly interact differentially with synaptic and extrasynaptic GABAARs, providing a potent novel context-dependent mechanism for regulation of inhibition.
| Original language | English |
|---|---|
| Pages (from-to) | 2440-2455 |
| Number of pages | 16 |
| Journal | Cerebral Cortex |
| Volume | 25 |
| Issue number | 9 |
| Early online date | 18 Mar 2014 |
| DOIs | |
| Publication status | Published - 1 Sep 2015 |
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Keywords
- Cb receptors
- DSI
- Endocannabinoids
- Fast-spiking interneurons
- Inhibitory synaptic transmission
- Neocortex
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Control of inhibition by the direct action of cannabinoids on GABAA receptors. / Golovko, Tatiana; Min, Rogier; Lozovaya, Natalia; Falconer, Caroline; Yatsenko, Natalia; Tsintsadze, Timur; Tsintsadze, Vera; Ledent, Catherine; Harvey, Robert J.; Belelli, Delia; Lambert, Jeremy J.; Rozov, Andrei; Burnashev, Nail (Lead / Corresponding author).
In: Cerebral Cortex, Vol. 25, No. 9, 01.09.2015, p. 2440-2455.Research output: Contribution to journal › Article
TY - JOUR
T1 - Control of inhibition by the direct action of cannabinoids on GABAA receptors
AU - Golovko, Tatiana
AU - Min, Rogier
AU - Lozovaya, Natalia
AU - Falconer, Caroline
AU - Yatsenko, Natalia
AU - Tsintsadze, Timur
AU - Tsintsadze, Vera
AU - Ledent, Catherine
AU - Harvey, Robert J.
AU - Belelli, Delia
AU - Lambert, Jeremy J.
AU - Rozov, Andrei
AU - Burnashev, Nail
N1 - This work was supported by International Brain Research Organization (IBRO), Research grant of the Netherlands Organisation for Scientific Research (NWO), and Marie Curie IIF 237781 “CANNABISTARG” grants to N.L. and Fondation pour la Recherche Médicale (FRM)—“Nouvelle Equipe’ grant to N.B.. The Department of Integrative Neurophysiology was financially supported by NeuroBsik (www.neurobsik.nl). Experiments on the α2−/− mouse were supported by the MRC (G1000008) to J.J.L. and D.B.).
PY - 2015/9/1
Y1 - 2015/9/1
N2 - Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB1 receptors (CB1Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABAA receptors (GABAARs), potentiating currents activated by micromolar concentrations of γ-aminobutyric acid (GABA). However, the impact of this direct interaction on GABAergic inhibition in central nervous system is unknown. Here we report that currents mediated by recombinant GABAARs activated by high (synaptic) concentrations of GABA as well as GABAergic inhibitory postsynaptic currents (IPSCs) at neocortical fast spiking (FS) interneuron to pyramidal neuron synapses are suppressed by exogenous and endogenous cannabinoids in a CB1R-independent manner. This IPSC suppression may account for disruption of inhibitory control of pyramidal neurons by FS interneurons. At FS interneuron to pyramidal neuron synapses, endocannabinoids induce synaptic low-pass filtering of GABAAR-mediated currents evoked by high-frequency stimulation. The CB1R-independent suppression of inhibition is synapse specific. It does not occur in CB1R containing hippocampal cholecystokinin-positive interneuron to pyramidal neuron synapses. Furthermore, in contrast to synaptic receptors, the activity of extrasynaptic GABAARs in neocortical pyramidal neurons is enhanced by cannabinoids in a CB1R-independent manner. Thus, cannabinoids directly interact differentially with synaptic and extrasynaptic GABAARs, providing a potent novel context-dependent mechanism for regulation of inhibition.
AB - Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB1 receptors (CB1Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABAA receptors (GABAARs), potentiating currents activated by micromolar concentrations of γ-aminobutyric acid (GABA). However, the impact of this direct interaction on GABAergic inhibition in central nervous system is unknown. Here we report that currents mediated by recombinant GABAARs activated by high (synaptic) concentrations of GABA as well as GABAergic inhibitory postsynaptic currents (IPSCs) at neocortical fast spiking (FS) interneuron to pyramidal neuron synapses are suppressed by exogenous and endogenous cannabinoids in a CB1R-independent manner. This IPSC suppression may account for disruption of inhibitory control of pyramidal neurons by FS interneurons. At FS interneuron to pyramidal neuron synapses, endocannabinoids induce synaptic low-pass filtering of GABAAR-mediated currents evoked by high-frequency stimulation. The CB1R-independent suppression of inhibition is synapse specific. It does not occur in CB1R containing hippocampal cholecystokinin-positive interneuron to pyramidal neuron synapses. Furthermore, in contrast to synaptic receptors, the activity of extrasynaptic GABAARs in neocortical pyramidal neurons is enhanced by cannabinoids in a CB1R-independent manner. Thus, cannabinoids directly interact differentially with synaptic and extrasynaptic GABAARs, providing a potent novel context-dependent mechanism for regulation of inhibition.
KW - Cb receptors
KW - DSI
KW - Endocannabinoids
KW - Fast-spiking interneurons
KW - Inhibitory synaptic transmission
KW - Neocortex
UR - http://www.scopus.com/inward/record.url?scp=84983335533&partnerID=8YFLogxK
U2 - 10.1093/cercor/bhu045
DO - 10.1093/cercor/bhu045
M3 - Article
C2 - 24646614
AN - SCOPUS:84983335533
VL - 25
SP - 2440
EP - 2455
JO - Cerebral Cortex
JF - Cerebral Cortex
SN - 1047-3211
IS - 9
ER -