Striatal GABAergic and cortical glutamatergic neurons mediate contrasting effects of cannabinoids on cortical network synchrony

Abstract

Activation of type 1 cannabinoid receptors (CB1R) decreases GABA and glutamate release in cortical and subcortical regions, with complex outcomes on cortical network activity. To date there have been few attempts to disentangle the region-and cell-specific mechanisms underlying the effects of cannabinoids on cortical network activity in vivo. Here we addressed this issue by combining in vivo electrophysiological recordings with local and systemic pharmacological manipulations in conditional mutant mice lacking CB1R expression in different neuronal populations. First we report that cannabinoids induce hypersynchronous thalamocortical oscillations while decreasing the amplitude of faster cortical oscillations. Then we demonstrate that CB1R at striatonigral synapses (basal ganglia direct pathway) mediate the thalamocortical hypersynchrony, whereas activation of CB1R expressed in cortical glutamatergic neurons decreases cortical synchrony. Finally we show that activation of CB1 expressed in cortical glutamatergic neurons limits the cannabinoid-induced thalamocortical hypersynchrony. By reporting that CB1R activations in cortical and subcortical regions have contrasting effects on cortical synchrony, our study bridges the gap between cellular and in vivo network effects of cannabinoids. Incidentally, the thalamocortical hypersynchrony we report suggests a potential mechanism to explain the sensory "high" experienced during recreational consumption of marijuana.annabinoids are a family of compounds that activate cannabinoid receptors, which are well known for their psychotropic effects and therapeutic potentials. The type 1 cannabinoid receptor (CB1R) is massively expressed in the brain at the synaptic terminals of excitatory and inhibitory neurons, and its activation by exogenous or endogenous cannabinoids decreases neurotransmitter release (1-3). One largely unanswered question is how the elementary decreases in excitatory and inhibitory synaptic transmissions induced by systemic intake of cannabinoids interact to produce alterations in neuronal network activity in vivo. A number of recent studies combining systemic injections of CB1R agonists and antagonists with electrophysiological recordings in the hippocampus and neocortex of awake or anesthetized rodents have shown that a hallmark of cannabinoids effects on neuronal network activity is a decrease in synchrony (4-9). Specifically, systemic CB1R activation has been shown to decrease (i) the amplitude of the hippocampal θ rhythm (4, 7, 8), (ii) the amplitude of γ oscillations in the hippocampus (4, 7, 10), enthorinal cortex (8), and prefrontal cortex (7), (iii) the incidence of hippocampal ripples (4, 6, 11), and (iv) spiking correlation in the hippocampus and prefrontal cortex (4,5,7,9).In contrast to the consistent reports that cannabinoids dampen cortical network oscillations, other findings suggest that they could also increase synchrony. First, CB1R are predominantly expressed by GABAergic forebrain neurons (12), and their activation leads to decreased GABA ...

Distribution of the Endocannabinoid System in the Central Nervous System

“…Agonist activation of CB 1 receptors on these interneurons was found to decrease power in theta, gamma, and ripple oscillations in the hippocampus (Robbe et al 2006). Actions of cannabinoids such as these appear to be widespread in cortical and subcortical circuits (Sales-Carbonell et al 2013) and may contribute to the effects of cannabinoids on memory (Chen et al 2003;Freund et al 2003;Klausberger et al 2005;Robbe et al 2006). Building on earlier studies that detected CB 1 mRNA, but not protein in CA1 and CA3 pyramidal neurons, studies in which CB 1 receptors were selectively deleted from either GABAergic or glutamatergic neurons allowed the conclusive anatomical identification of low levels of CB 1 protein in glutamatergic hippocampal pyramidal neurons (Marsicano et al 2003;Lutz 2004).…”

Adolescent Cannabinoid Exposure Permanently Suppresses Cortical Oscillations in Adult Mice

“…Acute cannabinoid exposure attenuates the power of neural oscillations recorded in vitro (Hajós et al, 2000(Hajós et al, , 2008 and in vivo, in freely moving animals (Robbe et al, 2006;Hajós et al, 2008;Kucewicz et al, 2011) and during working memory tasks (Kucewicz et al, 2011) by CB1R-mediated suppression of glutamate release from pyramidal neurons (Holderith et al, 2011;Sales-Carbonell et al, 2013). This CB1R-mediated attenuation of excitatory transmission preferentially suppresses the frequency and firing precision of fast-spiking GABAergic interneurons, resulting in smaller and less synchronized field potentials (Holderith et al, 2011).…”

“…Acute cannabinoid administration attenuates the power of oscillations (Hajós et al, 2000(Hajós et al, , 2008Robbe et al, 2006;Kucewicz et al, 2011) by acting at CB1Rs to suppress glutamate release from pyramidal neurons (Holderith et al, 2011;Sales-Carbonell et al, 2013). Furthermore, oscillations are suppressed in chronic marijuana users, particularly in those with an earlier age of onset of use (Skosnik et al, 2012).…”

Permanent suppression of cortical oscillations in mice after adolescent exposure to cannabinoids: Receptor mechanisms

“…These acute suppressive effects are mediated by the CB1R, as they can be antagonized by pre-treatment or co-administration of CB1R antagonists, such as AM251 or SR141716 (Robbe et al , 2006; Hajos et al , 2008; Holderith et al , 2011; Sales-Carbonell et al , 2013). Similarly, recent evidence indicates that 5 days of WIN exposure early in adolescence impairs the modulation of oscillatory local field potential (LFP) activity in mPFC evoked by ventral hippocampus stimulation, and that this impairment is mediated by the CB1R (Cass et al , 2014).…”