Cannabinoid receptor activation modifies NMDA receptor mediated release of intracellular calcium: Implications for endocannabinoid control of hippocampal neural plasticity

Abstract

Chronic activation or inhibition of cannabinoid receptors (CB1) leads to continuous suppression of neuronal plasticity in hippocampus and other brain regions, suggesting that endocannabinoids may have a functional role in synaptic processes that produce state-dependent transient modulation of hippocampal cell activity. In support of this, it has previously been shown in vitro that cannabinoid CB1 receptors modulate second messenger systems in hippocampal neurons that can modulate intracellular ion channels, including channels which release calcium from intracellular stores. Here we demonstrate in hippocampal slices a similar endocannabinoid action on excitatory glutamatergic synapses via modulation of NMDA-receptor mediated intracellular calcium levels in confocal imaged neurons. Calcium entry through glutamatergic NMDA-mediated ion channels increases intracellular calcium concentrations via modulation of release from ryanodine-sensitive channels in endoplasmic reticulum. The studies reported here show that NMDA-elicited increases in Calcium Green fluorescence are enhanced by CB1 receptor antagonists (i.e. rimonabant), and inhibited by CB1 agonists (i.e. WIN 55,212-2). Suppression of endocannabinoid breakdown by either reuptake inhibition (AM404) or fatty-acid amide hydrolase inhibition (URB597) produced suppression of NMDA elicited calcium increases comparable to WIN 55,212-2, while enhancement of calcium release provoked by endocannabinoid receptor antagonists (Rimonabant) was shown to depend on the blockade of CB1 receptor mediated de-phosphorylation of Ryanodine receptors. Such CB1 receptor modulation of NMDA elicited increases in intracellular calcium may account for the respective disruption and enhancement by CB1 agents of trial-specific hippocampal neuron ensemble firing patterns during performance of a short-term memory task, reported previously from this laboratory.

Chronic effects of cannabis on sensory gating

“…CB 1 receptors occur in high density throughout the brain, particularly in the hippocampus, anterior cingulate, basal ganglia and the cerebellum; regions which are involved in cognition and are particularly important for attention, learning and memory (Bhattacharyya et al, 2009;Bossong and Niesink, 2010;Iversen, 2004). Impaired cognition in chronic cannabis users is thought to be underpinned at least in part, by alterations to the regulatory role of the endocannabinoid system on synaptic plasticity following prolonged and regular exposure to exogenous cannabinoids such as THC (Hampson et al, 2011;Heifets and Castillo, 2009;Hoffman et al, 2007;Puighermanal et al, 2012). In light of deficits in cognition (e.g., selective attention, verbal learning and inhibition, Solowij and Michie, 2007), and alterations in brain function (e.g., prefrontal cortical, cingular, hippocampal and cerebellar activation in imaging studies, Solowij and Michie, 2007;Martin-Santos et al, 2010) and structure (e.g., reduced hippocampal volume, Yücel et al, 2008b) in long-term cannabis users being similar to those observed in patients with schizophrenia, further investigation of neurobiological markers of pre-attentive processes may inform mechanisms by which cannabis might result in schizophrenia-like conditions in the brain and induce psychosis in vulnerable individuals.…”

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

“…Studies have shown that systemically administered kainic acid (KA) treatment elevates AEA levels in the brain [14,[31][32][33]. Related to this response to injury, FAAH inhibition enhanced the salutary effects of cannabinergic signaling in the rat hippocampus, mediated predominantly via CB1 receptors [1,14,34,35]. It has been suggested that CB1 receptor activation reduces excessive glutamatergic signaling and excitotoxic progression thereby protecting hippocampal cells from cytoskeletal and synaptic damage [13,14,32,33,36].…”

Cannabinoids disrupt hippocampal sharp wave‐ripples via inhibition of glutamate release

“…Anatomically and functionally it is now well established that CB1 receptors are highly expressed at presynaptic terminals, where they contribute to inhibition of neurotransmitter release. This cannabinoid-mediated modulation of transmitter release has been shown to involve the regulation of Ca 21 entry into the cytosol (Hoffman and Lupica, 2000;Hampson et al, 2011; for review, see Wilson and Nicoll, 2002;Freund et al, 2003;Iversen, 2003;).…”