Search

Gi-coupled receptors, particularly cannabinoid receptors (CBRs), are considered perspective targets for treating brain pathologies, including epilepsy. However, the precise mechanism of the anticonvulsant effect of the CBR agonists remains unknown. We have found that WIN 55,212-2 (a CBR agonist) suppresses the synchronous oscillations of the intracellular concentration of Ca2+ ions (epileptiform activity) induced in the neurons of rat hippocampal neuron-glial cultures by bicuculline or NH4Cl. As we have demonstrated, the WIN 55,212-2 effect is mediated by CB1R receptors. The agonist suppresses Ca2+ inflow mediated by the voltage-gated calcium channels but does not alter the inflow mediated by NMDA, AMPA, and kainate receptors. We have also found that phospholipase C (PLC), protein kinase C (PKC), and G-protein-coupled inwardly rectifying K+ channels (GIRK channels) are involved in the molecular mechanism underlying the inhibitory action of CB1R activation against epileptiform activity. Thus, our results demonstrate that the antiepileptic action of CB1R agonists is mediated by different intracellular signaling cascades, including non-canonical PLC/PKC-associated pathways. [ABSTRACT FROM AUTHOR]

Calcium‐permeable AMPA receptors (CP‐AMPARs) play a pivotal role in brain functioning in health and disease. They are involved in synaptic plasticity, synaptogenesis, and neuronal circuits development. However, the functions of neurons expressing CP‐AMPARs and their role in the modulation of network activity remain elusive since reliable and accurate visualization methods are absent. Here we developed an approach allowing the vital identification of neurons containing CP‐AMPARs. The proposed method relies on evaluating Ca2+ influx in neurons during activation of AMPARs in the presence of NMDAR and KAR antagonists, and blockers of voltage‐gated Ca2+ channels. Using this method, we studied the properties of CP‐AMPARs‐containing neurons. We showed that the overwhelming majority of neurons containing CP‐AMPARs are GABAergic, and they are distinguished by higher amplitudes of the calcium responses to applications of the agonists. Furthermore, about 30% of CP‐AMPARs‐containing neurons demonstrate the presence of GluK1‐containing KARs. Although CP‐AMPARs‐containing neurons are characterized by more significant Ca2+ influx during the activation of AMPARs than other neurons, AMPAR‐mediated Na+ influx is similar in these two groups. We revealed that neurons containing CP‐AMPARs demonstrate weak GABA(A)R‐mediated inhibition because of the low percentage of GABAergic synapses on the soma of these cells. However, our data show that weak GABA(A)R‐mediated inhibition is inherent to all GABAergic neurons in the culture and cannot be considered a unique feature of CP‐AMPARs‐containing neurons. We believe that the suggested approach will help to understand the role of CP‐AMPARs in the mammalian nervous system in more detail. [ABSTRACT FROM AUTHOR]

Calcium-permeable AMPA receptors (CP-AMPARs) play a pivotal role in brain functioning in health and disease. They are involved in synaptic plasticity, synaptogenesis, and neuronal circuits development. However, the functions of neurons expressing CP-AMPARs and their role in the modulation of network activity remain elusive since reliable and accurate visualization methods are absent. Here we developed an approach allowing the vital identification of neurons containing CP-AMPARs. The proposed method relies on evaluating Ca 2+ influx in neurons during activation of AMPARs in the presence of NMDAR and KAR antagonists, and blockers of voltage-gated Ca 2+ channels. Using this method, we studied the properties of CP-AMPARs-containing neurons. We showed that the overwhelming majority of neurons containing CP-AMPARs are GABAergic, and they are distinguished by higher amplitudes of the calcium responses to applications of the agonists. Furthermore, about 30% of CP-AMPARs-containing neurons demonstrate the presence of GluK1-containing KARs. Although CP-AMPARs-containing neurons are characterized by more significant Ca 2+ influx during the activation of AMPARs than other neurons, AMPAR-mediated Na + influx is similar in these two groups. We revealed that neurons containing CP-AMPARs demonstrate weak GABA(A)R-mediated inhibition because of the low percentage of GABAergic synapses on the soma of these cells. However, our data show that weak GABA(A)R-mediated inhibition is inherent to all GABAergic neurons in the culture and cannot be considered a unique feature of CP-AMPARs-containing neurons. We believe that the suggested approach will help to understand the role of CP-AMPARs in the mammalian nervous system in more detail., (© 2022 International Society for Neurochemistry.)