scholarly journals Functional CB1 Receptors Are Broadly Expressed in Neocortical GABAergic and Glutamatergic Neurons

2007 ◽  
Vol 97 (4) ◽  
pp. 2580-2589 ◽  
Author(s):  
Elisa L. Hill ◽  
Thierry Gallopin ◽  
Isabelle Férézou ◽  
Bruno Cauli ◽  
Jean Rossier ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Physiological Data ◽  
Glutamatergic Neurons ◽  
Neuronal Populations ◽  
Postsynaptic Currents ◽  
Neocortical Neurons ◽  
Neuronal Types ◽  
Cb1 Antagonist ◽  
Whole Cell Recordings

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.

Endocannabinoids Mediate Rapid Retrograde Signaling At Interneuron → Pyramidal Neuron Synapses of the Neocortex

2003 ◽  
Vol 89 (4) ◽  
pp. 2334-2338 ◽  
Author(s):  
Joseph Trettel ◽  
Eric S. Levine
Keyword(s):  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Gaba Release ◽  
Inhibitory Interneurons ◽  
Strongly Correlated ◽  
Inhibitory Strength ◽  
Activity Dependent ◽  
Whole Cell Recordings

In the neocortex, inhibitory interneurons tightly regulate the firing patterns and integrative properties of pyramidal neurons (PNs). The endocannabinoid system of the neocortex may play an important role in the activity-dependent regulation of inhibitory (i.e., GABAergic) inputs received by PNs. In the present study, using whole cell recordings from layer 2/3 PNs in slices of mouse sensory cortex, we have identified a role for PN-derived endocannabinoids in the control of afferent inhibitory strength. Pairing evoked inhibitory currents with repeated epochs of postsynaptic depolarization led to a transient suppression of inhibition that was induced by a rise in postsynaptic Ca2+ and was expressed as a reduction in presynaptic GABA release. An antagonist (AM251) of the type-1 cannabinoid receptor blocked the depolarization-induced suppression of evoked inhibitory postsynaptic currents (eIPSCs), and the cannabinoid WIN55,212-2 reduced eIPSC amplitude and occluded suppression. The degree of WIN55,212-2-mediated inhibition of eIPSCs was strongly correlated with the magnitude of depolarization-induced suppression of the eIPSCs, suggesting that the WIN-sensitive afferents are suppressed by PN depolarization. Moreover, blocking endocannabinoid uptake with AM404 strongly modulated the kinetics and magnitude of eIPSC suppression. We conclude that the release of endocannabinoids from PNs allows for the postsynaptic control of presynaptic inhibition and could have profound consequences for the integrative properties of neocortical PNs.

scholarly journals Neuronal Dystroglycan regulates postnatal development of CCK/cannabinoid receptor-1 interneurons

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Daniel S. Miller ◽  
Kevin M. Wright
Keyword(s):  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Inhibitory Synapses ◽  
Proper Function ◽  
Mammalian Brain ◽  
Gabaergic Interneuron ◽  
Cannabinoid Receptor 1 ◽  
Neuronal Populations ◽  
Forebrain Development ◽  
Transmembrane Glycoprotein

Abstract Background The development of functional neural circuits requires the precise formation of synaptic connections between diverse neuronal populations. The molecular pathways that allow GABAergic interneuron subtypes in the mammalian brain to initially recognize their postsynaptic partners remain largely unknown. The transmembrane glycoprotein Dystroglycan is localized to inhibitory synapses in pyramidal neurons, where it is required for the proper function of CCK+ interneurons. However, the precise temporal requirement for Dystroglycan during inhibitory synapse development has not been examined. Methods In this study, we use NEXCre or Camk2aCreERT2 to conditionally delete Dystroglycan from newly-born or adult pyramidal neurons, respectively. We then analyze forebrain development from postnatal day 3 through adulthood, with a particular focus on CCK+ interneurons. Results In the absence of postsynaptic Dystroglycan in developing pyramidal neurons, presynaptic CCK+ interneurons fail to elaborate their axons and largely disappear from the cortex, hippocampus, amygdala, and olfactory bulb during the first two postnatal weeks. Other interneuron subtypes are unaffected, indicating that CCK+ interneurons are unique in their requirement for postsynaptic Dystroglycan. Dystroglycan does not appear to be required in adult pyramidal neurons to maintain CCK+ interneurons. Bax deletion did not rescue CCK+ interneurons in Dystroglycan mutants during development, suggesting that they are not eliminated by canonical apoptosis. Rather, we observed increased innervation of the striatum, suggesting that the few remaining CCK+ interneurons re-directed their axons to neighboring areas where Dystroglycan expression remained intact. Conclusion Together these findings show that Dystroglycan functions as part of a synaptic partner recognition complex that is required early for CCK+ interneuron development in the forebrain.

Characterization of pharmacologically identified voltage-gated calcium channel currents in acutely isolated rat neocortical neurons. II. Postnatal development

1995 ◽  
Vol 73 (4) ◽  
pp. 1443-1451 ◽  
Author(s):  
N. M. Lorenzon ◽  
R. C. Foehring
Keyword(s):  
Calcium Channel ◽  
Pyramidal Neurons ◽  
Companion Paper ◽  
Whole Cell ◽  
Time To Peak ◽  
Neocortical Neurons ◽  
P Type ◽  
Channel Currents ◽  
Whole Cell Recordings

1. Whole cell recordings were obtained from pyramidal neurons acutely dissociated from the sensorimotor cortex of adult (from Lorenzon and Foehring, companion paper) and immature rats postnatal day 1 (P1) to adult. 2. Whole cell calcium channel currents were similar in appearance at all ages. Current amplitudes and estimated densities were initially low (approximately 16 pA/pF at ages < P6) and increased gradually, attaining adult values at approximately 4-5 wk postnatally (approximately 100 pA/pF). 3. L-type current was operationally defined as that blocked by 5 microM nifedipine, N-type current as that blocked by 1 microM omega-conotoxin GVIA, and P-type current as that blocked by 100 nM omega-agatoxin IVA. A resistant current remained in the presence of the combination of these three blockers. The proportions of these four current types did not change during ontogeny. 4. Few biophysical differences were found between the pharmacologically defined current components in adult or 1-wk-old cells. At both ages the resistant current had a more rapid time-to-peak and inactivated more completely and rapidly than the other three types. Resistant currents also activated at more negative potentials. N-, L-, and P-type currents activated at more positive potentials in 1-wk-old cells than in adult cells. For the resistant current, the voltage dependence of activation was not significantly different between the two ages.

Lack of Depolarization-Induced Suppression of Inhibition (DSI) in Layer 2/3 Interneurons That Receive Cannabinoid-Sensitive Inhibitory Inputs

2007 ◽  
Vol 98 (5) ◽  
pp. 2517-2524 ◽  
Author(s):  
Fouad Lemtiri-Chlieh ◽  
Eric S. Levine
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Brain Slices ◽  
Gaba Release ◽  
Synaptic Activity ◽  
Layer 2 ◽  
Fast Spiking ◽  
Whole Cell Recordings

In layer 2/3 of neocortex, brief trains of action potentials in pyramidal neurons (PNs) induce the mobilization of endogenous cannabinoids (eCBs), resulting in a depression of GABA release from the terminals of inhibitory interneurons (INs). This depolarization-induced suppression of inhibition (DSI) is mediated by activation of the type 1 cannabinoid receptor (CB1) on presynaptic terminals of a subset of INs. However, it is not clear whether CB1 receptors are also expressed at synapses between INs, and whether INs can release eCBs in response to depolarization. In the present studies, brain slices containing somatosensory cortex were prepared from 14- to 21-day-old CD-1 mice. Whole cell recordings were obtained from layer 2/3 PNs and from INs classified as regular spiking nonpyramidal, irregular spiking, or fast spiking. For all three classes of INs, the cannabinoid agonist WIN55,212-2 suppressed inhibitory synaptic activity, similar to the effect seen in PNs. In addition, trains of action potentials in PNs resulted in significant DSI. In INs, however, DSI was not seen in any cell type, even with prolonged high-frequency spike trains that produced calcium increases comparable to that seen with DSI induction in PNs. In addition, blocking eCB reuptake with AM404, which enhanced DSI in PNs, failed to unmask any DSI in INs. Thus the lack of DSI in INs does not appear to be due to an insufficient increase in intracellular calcium or enhanced reuptake. These results suggest that layer 2/3 INs receive CB1-expressing inhibitory inputs, but that eCBs are not released by these INs.

scholarly journals Neuronal Dystroglycan regulates postnatal development of CCK/cannabinoid receptor-1 interneurons

2021 ◽  
Author(s):  
Daniel S Miller ◽  
Kevin M Wright
Keyword(s):  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Inhibitory Synapses ◽  
Proper Function ◽  
Mammalian Brain ◽  
Gabaergic Interneuron ◽  
Cannabinoid Receptor 1 ◽  
Neuronal Populations ◽  
Transmembrane Glycoprotein ◽  
Interneuron Development

The development of functional neural circuits requires the precise formation of synaptic connections between diverse neuronal populations. The molecular pathways that allow GABAergic interneuron subtypes in the mammalian brain to recognize their postsynaptic partners remain largely unknown. The transmembrane glycoprotein Dystroglycan is localized to inhibitory synapses in pyramidal neurons, where it is required for the proper function of CCK+ interneurons. We show that deletion of Dystroglycan from pyramidal neurons selectively impairs CCK+ interneuron development during the first postnatal week. In the absence of postsynaptic Dystroglycan, presynaptic CCK+ interneurons fail to elaborate their axons and largely disappear from the cortex, hippocampus, amygdala, and olfactory bulb. Bax deletion did not rescue CCK+ interneurons, suggesting that they are not eliminated by canonical apoptosis in Dystroglycan mutants. Rather, we observed an increase in CCK+ interneuron innervation of the striatum, suggesting that the remaining CCK+ interneurons re-directed their axons to neighboring areas where Dystroglycan expression remained intact. Together these findings identify Dystroglycan as a critical regulator of CCK+ interneuron development.

scholarly journals Cannabinoids Depress Inhibitory Synaptic Inputs Received by Layer 2/3 Pyramidal Neurons of the Neocortex

2002 ◽  
Vol 88 (1) ◽  
pp. 534-539 ◽  
Author(s):  
Joseph Trettel ◽  
Eric S. Levine
Keyword(s):  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Cell Voltage ◽  
Gaba Release ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Presynaptic Site ◽  
Layer 2 ◽  
Kinetics Of

Using whole cell voltage-clamp recordings we investigated the effects of a synthetic cannabinoid (WIN55,212-2) on inhibitory inputs received by layer 2/3 pyramidal neurons in slices of the mouse auditory cortex. Activation of the type 1 cannabinoid receptor (CB1R) with WIN55,212-2 reliably reduced the amplitude of GABAergic inhibitory postsynaptic currents evoked by extracellular stimulation within layer 2/3. The suppression of this inhibition was blocked and reversed by the highly selective CB1R antagonist AM251, confirming a CB1R-mediated inhibition. Pairing evoked inhibitory postsynaptic currents (IPSCs) at short interstimulus intervals while applying WIN55,212-2 resulted in an increase in paired-pulse facilitation suggesting that the probability of GABA release was reduced. A presynaptic site of cannabinoid action was verified by an observed decrease in the frequency with no change in the amplitude or kinetics of action potential–independent postsynaptic currents (mIPSCs). When Cd2+ was added or Ca2+ was omitted from the recording solution, the remaining fraction of Ca2+-independent mIPSCs did not respond to WIN55,212-2. These data suggest that cannabinoids are capable of suppressing the inhibition of neocortical pyramidal neurons by depressing Ca2+-dependent GABA release from local interneurons.

Postnatal development of a persistent Na+ current in pyramidal neurons from rat sensorimotor cortex

1993 ◽  
Vol 69 (1) ◽  
pp. 290-292 ◽  
Author(s):  
C. Alzheimer ◽  
P. C. Schwindt ◽  
W. E. Crill
Keyword(s):  
Postnatal Development ◽  
Sensorimotor Cortex ◽  
Pyramidal Neurons ◽  
Direct Evidence ◽  
Fold Increase ◽  
Na Current ◽  
Early Postnatal Development ◽  
Neocortical Neurons ◽  
Voltage Dependent ◽  
Whole Cell Recordings

1. Whole-cell recordings were performed on acutely isolated pyramidal neurons from rat sensorimotor cortex 2 to 21 days postnatal to study the expression of a tetrodotoxin (TTX) sensitive, voltage dependent, persistent Na+ current (INaP) during different stages of postnatal development. 2. INaP was activated positive to about -60 mV and attained its peak amplitude between -40 and -35 mV. Activation of INaP did not require preceding activation of the transient Na+ current. 3. Peak INaP amplitudes showed a three-fold increase over the first three postnatal weeks, starting from 60.7 +/- 7.5 (SE) pA (n = 6) at postnatal day (P) 2-P5 and reaching 189.1 +/- 20.4 pA (n = 13) at P17–P21. 4. Measurements of peak INaP density, which took concomitant cell growth into account, revealed that a considerable current density already existed in very young neurons (P2–P5: 4.3 +/- 1.0 microA/cm2, n = 6) when compared with INaP density in early adult neurons (P17 - P21: 8.9 +/- 0.8 microA/cm2, n = 5). 5. Our data provide the first direct evidence for the presence of a significant INaP density during early postnatal development of neocortical neurons indicating that this current should play a role in the control of intrinsic excitability at this age.

scholarly journals Tricyclic Pyrazole-Based Compounds as Useful Scaffolds for Cannabinoid CB1/CB2 Receptor Interaction

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2126
Author(s):  
Battistina Asproni ◽  
Gabriele Murineddu ◽  
Paola Corona ◽  
Gérard A. Pinna
Keyword(s):  
Neuropathic Pain ◽  
Cannabinoid Receptor ◽  
Receptor Interaction ◽  
Pharmacological Properties ◽  
Cb2 Receptor ◽  
Antiemetic Effect ◽  
High Affinity ◽  
Cb1 Antagonist ◽  
Cb2 Receptors ◽  
Sar Study

Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include analgesic activity, bodyweight reduction, the antiemetic effect, the reduction of intraocular pressure and many others, which appear correlated to the affinity of cannabinoids towards CB1 and/or CB2 receptors. Within the search aiming to identify novel chemical scaffolds for cannabinoid receptor interaction, the CB1 antagonist/inverse agonist pyrazole-based derivative rimonabant has been modified, giving rise to several tricyclic pyrazole-based compounds, most of which endowed of high affinity and selectivity for CB1 or CB2 receptors. The aim of this review is to present the synthesis and summarize the SAR study of such tricyclic pyrazole-based compounds, evidencing, for some derivatives, their potential in the treatment of neuropathic pain, obesity or in the management of glaucoma.

Metabotropic glutamate receptor-mediated suppression of L-type calcium current in acutely isolated neocortical neurons

1992 ◽  
Vol 68 (3) ◽  
pp. 833-842 ◽  
Author(s):  
R. J. Sayer ◽  
P. C. Schwindt ◽  
W. E. Crill
Keyword(s):  
Glutamate Receptor ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
High Threshold ◽  
External Application ◽  
Metabotropic Glutamate ◽  
Neocortical Neurons ◽  
Old Rats ◽  
Low Threshold ◽  
Ca2 Channels

1. The effects of metabotropic glutamate receptor (mGluR) stimulation on whole-cell Ca2+ currents were studied in pyramidal neurons isolated from the dorsal frontoparietal neocortex of rat. The selective mGluR agonist cis-(+/-)-1-aminocyclopentane-1,3-dicarboxylic acid [trans-ACPD (100 microM)] suppressed the peak high-threshold Ca2+ current by 21 +/- 1.7% (mean +/- SE) in 40 of 43 cells from 10- to 21-day-old rats. Consistent with previous findings for mGluR, glutamate, quisqualate, and ibotenate [but not alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)] reduced the Ca2+ currents, and the responses were not blocked by the ionotropic glutamate receptor antagonists 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonovaleric acid (APV). EC50S for Ca2+ current suppression were 29 nM for quisqualate, 2.3 microM for glutamate, and 13 microM for trans-ACPD. 2. The low-threshold Ca2+ current was not modulated by trans-ACPD. The component of the high-threshold CA2+ current suppressed by mGluR was determined by pharmacology; the responses were not affected by omega-conotoxin GVIA but were occluded by the dihydropyridine Ca2+ antagonist nifedipine. Ca2+ tail currents prolonged by the dihydropyridine Ca2+ agonist (+)-SDZ 202-79] were suppressed by mGluR stimulation in parallel with the peak current. These findings strongly suggest that L-type Ca2+ channels are modulated by mGluR. 3. In neurons dialyzed with 100 microM guanosine 5'-(gamma-thio)triphosphate (GTP-gamma-S), Ca2+ current suppression was elicited by the first application of trans-ACPD (in 5 of 6 cells), but not by subsequent applications. Responses in neurons dialyzed with 2 mM guanosine 5'-(beta-thio)diphosphate (GDP-beta-S) were significantly smaller than controls. The results are consistent with mGluR acting via linkage to a G protein. 4. The responses to mGluR agonists were smaller when the external Ca2+ was replaced by Ba2+, indicating that some part of the mechanism underlying the current suppression is Ca2+ dependent. Because mGluR stimulates phosphoinositide turnover and release of Ca2+ from intracellular stores in other types of neurons, the possibility of released Ca2+ mediating inactivation of Ca2+ channels was considered. However, the Ca2+ current suppression was not attenuated by strong intracellular Ca2+ buffering [20 mM bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA)], by dialysis with 100 microM inositol-1,4,5-triphosphate (IP3), or by external application of 1 microM thapsigargin. 5. We conclude that in neocortical neurons, one action of mGluR is to suppress the component of high-threshold Ca2+ current conducted by L-type Ca2+ channels.(ABSTRACT TRUNCATED AT 400 WORDS)

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