Somatic and terminal CB1 receptors are differentially coupled to voltage-gated sodium channels in neocortical neurons

Abstract

Endogenous cannabinoid signaling is vital for important brain functions and can be modified pharmacologically to treat pain, epilepsy, and posttraumatic stress disorder. Endocannabinoid mediated changes to excitability are predominantly attributed to 2-arachidonoylglycerol at synapses. Here we identify a pathway in the neocortex by which anandamide, the other major endocannabinoid, powerfully inhibits sodium conductances in the soma resulting in a loss of neuronal excitability. This pathway is mediated by the cannabinoid receptor, and its activation results in a decrease of recurrent action potential generation. The synthetic cannabinoid, Win-55, also inhibits VGSC currents indicating this pathway is positioned to mediate the actions of exogenous cannabinoids.

Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH‐018 in male mice

“…The evidence of an increased neuronal excitability seen in electrophysiological studies in the hippocampus may be related indirectly to this CB 1 downregulation. Indeed, it has been recently demonstrated that, in neocortical neurons, the activation of CB 1 receptors inhibits voltage gated sodium channels, reducing with high efficacy the neuronal excitability (Steiger et al, 2023).…”

Direct whole-cell patch-clamp recordings from small boutons in rodent primary neocortical neuron cultures

“…The protocol below has been developed and optimized for bouton recordings in mouse primary neocortical neuron-glia co-cultures (referred to as neocortical cultures below). 1 , 2 We first describe preparatory steps for bouton recordings, including the required equipment and solutions. Subsequently, we describe how low-capacitance quartz glass pipettes are manufactured, which are optimally suited for bouton recordings.…”

“…Finally, we describe errors related to pipette capacitance and how to achieve optimal pipette capacitance compensation required for high-resolution bouton recordings. We have successfully used this protocol for bouton recordings in mouse primary neocortical cultures and rat acute neocortical brain slices 1 , 2 and for dopaminergic axon recordings in rat acute striatal brain slices. 3 Furthermore, we are currently adapting this protocol for bouton recordings in rat hippocampal cultures and human iPSC-derived neuronal cultures.…”