Abstract
Cannabinoid receptor 1 (CB1R) is widely distributed in the central nervous system, in excitatory and inhibitory neurons, and in astrocytes. CB1R agonists impair cognition and prevent long-term potentiation (LTP) of synaptic transmission, but the influence of endogenously formed cannabinoids (eCBs) on hippocampal LTP remains ambiguous. Based on the knowledge that eCBs are released upon high frequency neuronal firing, we hypothesized that the influence of eCBs upon LTP could change according to the paradigm of LTP induction. We thus tested the influence of eCBs on hippocampal LTP using two θ-burst protocols that induce either a weak or a strong LTP. LTP induced by a weak-θ-burst protocol is facilitated while preventing the endogenous activation of CB1Rs. In contrast, the same procedures lead to inhibition of LTP induced by the strong-θ-burst protocol, suggestive of a facilitatory action of eCBs upon strong LTP. Accordingly, an inhibitor of the metabolism of the predominant eCB in the hippocampus, 2-arachidonoyl-glycerol (2-AG), facilitates strong LTP. The facilitatory action of endogenous CB1R activation does not require the activity of inhibitory A1 adenosine receptors, is not affected by inhibition of astrocytic metabolism, but involves inhibitory GABAergic transmission. The continuous activation of CB1Rs via exogenous cannabinoids, or by drugs known to prevent metabolism of the non-prevalent hippocampal eCB, anandamide, inhibited LTP. We conclude that endogenous activation of CB1Rs by physiologically formed eCBs exerts a fine-tune homeostatic control of LTP in the hippocampus, acting as a high-pass filter, therefore likely reducing the signal-to-noise ratio of synaptic strengthening.
Highlights
The influence of marijuana upon human cognition mostly results from its ability to interfere with the action of endocannabinoids in the brain. eCBs are widely recognized as fine-tune modulators of synaptic activity, their action mainly resulting from activation of G proteincoupled cannabinoid receptor type 1 receptors (CB1R), which are widely distributed in the central nervous system, in particular in the hippocampus, cortex, basal ganglia, and cerebellum
CB1Rs are endogenously activated by eCBs, mainly the fatty acid derivatives 2-arachidonoyl-sn-glycerol (2-AG) and anandamide. eCB synthesis mostly results from cleavage of postsynaptic membrane lipids as a consequence of the activation of postsynaptic G-coupled glutamate metabotropic receptors, which are predominantly activated as a consequence of high rate of neuronal firing (Chevaleyre et al, 2006; Katona et al, 2006). eCBs travel in a retrograde manner to activate astrocytic and nerve-terminal located CB1R, resulting in inhibition of neurotransmitter release, and giving rise to several forms of short-term synaptic plasticity (Freund et al, 2003; Chevaleyre et al, 2006; Kano et al, 2009; Ohno-Shosaku et al, 2012)
The adenosine A1 receptor knockout (A1R−/−) and wild-type (A1R+/+) mice were generated by inactivating the second protein coding exon of the mouse A1R gene, from heterozygous breeding pairs with C57Bl6/J background strain (Johansson et al, 2001), obtained from a breeding colony derived from this original line that is housed at Karolinska Institutet, Sweden, and genotyped as described previously (Yang et al, 2015)
Summary
The influence of marijuana upon human cognition mostly results from its ability to interfere with the action of endocannabinoids (eCBs) in the brain. eCBs are widely recognized as fine-tune modulators of synaptic activity, their action mainly resulting from activation of G proteincoupled cannabinoid receptor type 1 receptors (CB1R), which are widely distributed in the central nervous system, in particular in the hippocampus, cortex, basal ganglia, and cerebellumEndocannabinoids and LTP (Herkenham et al, 1991; Matsuda et al, 1993; Tsou et al, 1998; Marsicano and Lutz, 1999; Wilson and Nicoll, 2002). Considering only the hippocampus, a brain area important for memory encoding and the mostly used to study synaptic plasticity phenomena, there are reports showing that eCBs restrict LTP (Bohme et al, 1999; Slanina et al, 2005) while others show that they facilitate LTP (Carlson et al, 2002; De Oliveira Alvares et al, 2006) This is intriguing since LTP is a compelling cellular model for learning and memory (see Nicoll, 2017), and exogenous cannabinoids, including the phytocannabinoids present in marijuana and the synthetic CB1Rs agonists, have a negative impact upon learning and memory in humans and in laboratory animals (Miller et al, 1977; Lane et al, 2005; Sousa et al, 2011; Mouro et al, 2017). ECBs likely reduce the signal-to-noise ratio of activity-dependent synaptic strengthening at the CA1 area of the hippocampus
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