Cannabinoid Sensitivity and Synaptic Properties of 2 GABAergic Networks in the Neocortex (original) (raw)
Related papers
The Journal of Physiology, 2011
Non-technical summary Administration of cannabinoids can impair several cognitive functions, including memory by altering synchronous activities in cortical networks. We show that the gamma frequency (40 Hz) oscillations in hippocampal slices, that are prominent oscillations in electroencephalogram during awake states in vivo, are reduced by cannabinoids. This effect can be explained by the suppression of the excitatory synaptic transmission onto fast spiking basket cells, GABAergic cells that are key players in oscillogenesis. The reduced excitatory drive onto these interneurons leads to a reduction in neuronal firing frequency and precision, and thus to smaller field potentials. Our data further our understanding of the synaptic mechanisms of how cannabinoids alter neuronal operation.
GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus
Neuroscience, 2000
Cannabinoids have been shown to disrupt memory processes in mammals including humans. Although the CB1 neuronal cannabinoid receptor was identified several years ago, neuronal network mechanisms mediating cannabinoid effects are still controversial in animals, and even more obscure in humans. In the present study, the localization of CB1 receptors was investigated at the cellular and subcellular levels in the human hippocampus, using control post mortem and epileptic lobectomy tissue. The latter tissue was also used for [ 3 H]GABA release experiments, testing the predictions of the anatomical data. Detectable expression of CB1 was confined to interneurons, most of which were found to be cholecystokinin-containing basket cells. CB1positive cell bodies showed immunostaining in their perinuclear cytoplasm, but not in their somadendritic plasmamembrane. CB1immunoreactive axon terminals densely covered the entire hippocampus, forming symmetrical synapses characteristic of GABAergic boutons. Human temporal lobectomy samples were used in the release experiments, as they were similar to the controls regarding cellular and subcellular distribution of CB1 receptors. We found that the CB1 receptor agonist, WIN 55,212-2, strongly reduced [ 3 H]GABA release, and this effect was fully prevented by the specific CB1 receptor antagonist SR 141716A.
Journal of Neurophysiology, 2004
GABAergic synapses that is initiated by the calcium-and depolarization-dependent release of endocannabinoids from postsynaptic neurons. In the neocortex, pyramidal neurons (PNs) appear to use DSI as a mechanism for regulating somatic inhibition from a subpopulation of GABAergic inputs that express the type 1 cannabinoid receptor. Although postsynaptic control of afferent inhibition may directly influence the integrative properties of neocortical PNs, little is known regarding the patterns of activity that evoke endocannabinoid release and the impact such disinhibition may have on the excitability of PNs. Here we provide the first systematic survey of AP-induced DSI in the neocortex. The magnitude and time course of DSI was directly related to the number and frequency of postsynaptic APs and was enhanced in the presence of the cholinergic receptor agonist carbachol. This AP-induced DSI was mediated by endocannabinoids, as it was prevented by the cannabinoid receptor antagonist AM251 and potentiated by the endocannabinoid transport inhibitor AM404. We also explored the consequences of neocortical DSI on PN excitability by examining the responsiveness of PNs to evoked synaptic stimulation. We found that endocannabinoid-mediated DSI markedly increased PN responsiveness to excitatory synaptic inputs and promoted AP discharge with a time course that paralleled DSI expression. Taken together, our data suggest a role for endocannabinoids in regulating the output of cortical PNs.
CB1 cannabinoid receptor-mediated plasticity of GABAergic synapses in the mouse insular cortex
Scientific Reports
The insular cortex plays pivotal roles in taste learning. As cellular mechanisms of taste learning, long-term potentiation (LTP) at glutamatergic synapses is well studied. However, little is known about long-term changes of synaptic efficacy at GABAergic synapses in the insular cortex. Here, we examined the synaptic mechanisms of long-term plasticity at GABAergic synapses in layer V pyramidal neurons of the mouse insular cortex. In response to a prolonged high-frequency stimulation (HFS), GABAergic synapses displayed endocannabinod (eCB)-mediated long-term depression (LTD GABA ). When cannabinoid 1 receptors (CB1Rs) were blocked by a CB1R antagonist, the same stimuli caused LTP at GABAergic synapses (LTP GABA ) which was mediated by production of nitric oxide (NO) via activation of NMDA receptors. Intriguingly, NO signaling was necessary for the induction of LTD GABA . In the presence of leptin which blocks CB1 signaling, the prolonged HFS caused LTP GABA which was mediated by NO signaling. These results indicate that long-term plasticity at GABAergic synapses in the insular cortex can be modulated by combined effects of eCB and NO signaling. These forms of GABAergic synaptic plasticity in the insular cortex may be crucial synaptic mechanisms in taste learning.
Endocannabinoid-Mediated Control of Synaptic Transmission
Physiological Reviews, 2009
The cannabinoid receptor CB1 is found in abundance in brain neurons, whereas CB2 is essentially expressed outside the brain. In the neocortex, CB1 is observed predominantly on large cholecystokinin (CCK)-expressing interneurons. However, physiological evidence suggests that functional CB1 are present on other neocortical neuronal types. We investigated the expression of CB1 and CB2 in identified neurons of rat neocortical slices using single-cell RT-PCR. We found that 63% of somatostatin (SST)-expressing and 69% of vasoactive intestinal polypeptide (VIP)-expressing interneurons co-expressed CB1. As much as 49% of pyramidal neurons expressed CB1. In contrast, CB2 was observed in a small proportion of neocortical neurons. We performed whole cell recordings of pyramidal neurons to corroborate our molecular findings. Inhibitory postsynaptic currents (IPSCs) induced by a mixed muscarinic/nicotinic cholinergic agonist showed depolarization-induced suppression of inhibition and were decreased by the CB1 agonist WIN-55212-2 (WIN-2), suggesting that interneurons excited by cholinergic agonists (mainly SST and VIP neurons) possess CB1. IPSCs elicited by a nicotinic receptor agonist were also reduced in the presence of WIN-2, suggesting that neurons excited by nicotinic agonists (mainly VIP neurons) indeed possess CB1. WIN-2 largely decreased excitatory postsynaptic currents evoked by intracortical electrical stimulation, pointing at the presence of CB1 on glutamatergic pyramidal neurons. All WIN-2 effects were strongly reduced by the CB1 antagonist AM 251. We conclude that CB1 is expressed in various neocortical neuronal populations, including glutamatergic neurons. Our combined molecular and physiological data suggest that CB1 widely mediates endocannabinoid effects on glutamatergic and GABAergic transmission to modulate cortical networks. Auclair N, Otani S, Soubrie P, Crepel F. Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons. J Neurophysiol 83: 3287-3293, 2000. Bacci A, Huguenard JR, Prince DA. Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. Nature 431: 312-316, 2004. Bayraktar T, Welker E, Freund TF, Zilles K, Staiger JF. Neurons immunoreactive for vasoactive intestinal polypeptide in the rat primary somatosensory cortex: morphology and spatial relationship to barrel-related columns.
European Journal of Neuroscience, 2010
The influence of local circuit interneurons is thought to play an important role in adjusting synaptic strength via endogenous cannabinoid type 1 (CB1) receptors. Using paired whole-cell recordings, combined with double immunofluorescence and biocytin labelling in acute slices of rat CA1 at postnatal day 18-23, we investigated the properties of Cholecystokinin (CCK)-positive stratum radiatum local circuit interneuron connections that utilised CB1 receptors. Three types of synaptic connections were studied, lacunosum-moleculare-radiatum perforant path-associated (LM-R PPA) to Shaffer collateral-associated (SCA) interneurons, SCA-SCA interneurons and SCA-pyramidal cells. These three synapses were differentially under tonic reduction of inhibition that was blocked by the CB1 receptor inverse agonist AM-251 (10 lm), which enhanced IPSPs. The strength of tonic reduction of inhibition was correlated with asynchronous release which was apparent at connections among interneurons. AM-251 increased the ratio of synchronous to asynchronous release (synchronicity ratio), while the CB receptor agonist anandamide (14 lm) decreased the synchronicity ratio. Fast and slow calcium chelators (BAPTA-AM and EGTA-AM) also increased the synchronicity ratio, accelerated inhibitory time courses and reduced IPSP amplitudes. These data suggest that CB1 receptors at connections among interneuron synapses play a role in tonic suppression of inhibition and govern the asynchronous release of GABA, modulating the time windows of inhibition. Effects of calcium chelators suggest that asynchronous release is a result of a long-lasting presynaptic calcium transients and ⁄ or a large distance between calcium source and sensor of exocytosis. These properties of specialised inhibitory neurons may have important modulatory roles in controlling spike timing among local circuit interneurons.
Control of Inhibition by the Direct Action of Cannabinoids on GABAAReceptors
Cerebral Cortex, 2014
Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB 1 receptors (CB 1 Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABA A receptors (GABA A Rs), 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 GABA A Rs 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 CB 1 R-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 GABA A R-mediated currents evoked by high-frequency stimulation. The CB 1 R-independent suppression of inhibition is synapse specific. It does not occur in CB 1 R containing hippocampal cholecystokinin-positive interneuron to pyramidal neuron synapses. Furthermore, in contrast to synaptic receptors, the activity of extrasynaptic GABA A Rs in neocortical pyramidal neurons is enhanced by cannabinoids in a CB 1 R-independent manner. Thus, cannabinoids directly interact differentially with synaptic and extrasynaptic GABA A Rs, providing a potent novel context-dependent mechanism for regulation of inhibition.
Hippocampus, 2014
A subpopulation of GABAergic cells in cortical structures expresses CB 1 cannabinoid receptors (CB 1) on their axon terminals. In order to understand the function of these interneurons in information processing, it is necessary to uncover how they are embedded into neuronal circuits. Therefore, the proportion of GABAergic terminals expressing CB 1 and the morphological and electrophysiological properties of CB 1-immunoreactive interneurons should be revealed. We investigated the ratio and the origin of CB 1-expressing inhibitory boutons in the CA3 region of the hippocampus. Using immunocytochemical techniques, we estimated that approximately 40 % of GABAergic axon terminals in different layers of CA3 also expressed CB 1. To identify the inhibitory cell types expressing CB 1 in this region, we recorded and intracellularly-labeled interneurons in hippocampal slices. CB 1-expressing interneurons showed distinct axonal arborization, and were classified as basket cells, mossyfiber-associated cells, dendritic-layer-innervating cells or perforant-path-associated cells. In each morphological category, a substantial variability in axonal projection was observed. In contrast to the diverse morphology, the active and passive membrane properties were found to be rather similar. Using paired recordings, we found that pyramidal cells displayed large and fast unitary postsynaptic currents in response to activating basket and mossy-fiber-associated cells, while they showed slower and smaller synaptic events in pairs originating from interneurons that innervate the dendritic layer, which may be due to dendritic filtering. In addition, CB 1 activation significantly reduced the amplitude of the postsynaptic currents in each cell pair tested. Our data suggest that CB 1-expressing interneurons with different axonal projections have comparable physiological characteristics, contributing to a similar proportion of GABAergic inputs along the somato-dendritic axis of CA3 pyramidal cells.
1999
To understand the functional significance and mechanisms of action in the CNS of endogenous and exogenous cannabinoids, it is crucial to identify the neural elements that serve as the structural substrate of these actions. We used a recently developed antibody against the CB1 cannabinoid receptor to study this question in hippocampal networks. Interneurons with features typical of basket cells showed a selective, intense staining for CB1 in all hippocampal subfields and layers. Most of them (85.6%) contained cholecystokinin (CCK), which corresponded to 96.9% of all CCK-positive interneurons, whereas only 4.6% of the parvalbumin (PV)-containing basket cells expressed CB1. Accordingly, electron microscopy revealed that CB1-immunoreactive axon terminals of CCK-containing basket cells surrounded the somata and proximal dendrites of pyramidal neurons, whereas PV-positive basket cell terminals in similar locations were negative for CB1. The synthetic cannabinoid agonist WIN 55,212-2 (0.01-3 M) reduced dose-dependently the electrical field stimulation-induced [ 3 H]GABA release from superfused hippocampal slices, with an EC 50 value of 0.041 M. Inhibition of GABA release by WIN 55,212-2 was not mediated by inhibition of glutamatergic transmission because the WIN 55,212-2 effect was not reduced by the glutamate blockers AP5 and CNQX. In contrast, the CB1 cannabinoid receptor antagonist SR 141716A (1 M) prevented this effect, whereas by itself it did not change the outflow of [ 3 H]GABA.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
Depolarization-induced suppression of inhibition (DSI) is a form of short-term plasticity of GABAergic synaptic transmission that is found in cerebellar Purkinje cells and hippocampal CA1 pyramidal cells. DSI involves the release of a calcium-dependent retrograde messenger by the somatodendritic compartment of the postsynaptic cell. Both glutamate and endogenous cannabinoids have been proposed as retrograde messenger. Here we show that, in cerebellar parasagittal slices, type 1 cannabinoid receptors (CB1Rs) are expressed at high levels in axons of GABAergic interneurons and in presynaptic terminals onto Purkinje cells. Application of the cannabinoid antagonist AM-251 (500 nm) leads to the abolition of the DSI of evoked currents (eIPSCs) recorded in paired recordings and to a strong reduction of the DSI of TTX-insensitive miniature events (mIPSCs) recorded from Purkinje cells. Furthermore, the CB1R agonist WIN 55-212,2 (5 microm) induces a presynaptic inhibition of synaptic currents ...