Abstract
Endocannabinoids (eCBs), which include 2-arachidonoylglycerol (2-AG) and anandamide (AEA) are lipid signaling molecules involved in the regulation of an array of behavioral and physiological functions. Released by postsynaptic neurons, eCBs mediate both phasic and tonic signaling at central synapses. While the roles of phasic eCB signaling in modulating synaptic functions and plasticity are well characterized, very little is known regarding the physiological roles and mechanisms regulating tonic eCB signaling at central synapses. In this study, we show that both 2-AG and AEA are constitutively released in the dorsal raphe nucleus (DRN), where they exert tonic control of glutamatergic synaptic transmission onto serotonin (5-HT) neurons. The magnitude of this tonic eCB signaling is tightly regulated by the overall activity of neuronal network. Thus, short term in vitro neuronal silencing or blockade of excitatory synaptic transmission abolishes tonic eCB signaling in the DRn. Importantly, in addition to controlling basal synaptic transmission, this study reveals that tonic 2-AG, but not AEA signaling, modulates synaptic plasticity. Indeed, short-term increase in tonic 2-AG signaling impairs spike-timing dependent potentiation (tLTP) of glutamate synapses. This tonic 2-AG-mediated homeostatic control of DRN glutamate synapses is not signaled by canonical cannabinoid receptors, but by intracellular peroxisome proliferator-activated receptor gamma (PPARγ). Further examination reveals that 2-AG mediated activation of PPARγ blocks tLTP by inhibiting nitric oxide (NO), soluble guanylate cyclase, and protein kinase G (NO/sGC/PKG) signaling pathway. Collectively, these results unravel novel mechanisms by which tonic 2-AG signaling integrates network activities and controls the synaptic plasticity in the brain.
Highlights
In the brain, neurons dynamically regulate the strength of their synaptic inputs by adjusting the parameters of synaptic transmission using various signaling molecules, including endocannabinoids, a family of neuroactive lipids (Castillo et al, 2012)
To examine the role of tonic eCB signaling in controlling glutamatergic synaptic transmission onto dorsal raphe nucleus (DRN) 5-HT neurons, we performed ex-vivo whole-cell patch-clamp recordings from putative DRN 5-HT neurons and assessed the impact of the cannabinoid 1 receptors (CB1Rs) antagonist/inverse agonist AM 251 on the baseline amplitude of evoked excitatory postsynaptic currents
The increase of evoked excitatory postsynaptic currents (eEPSCs) amplitude was accompanied with a significant decrease in coefficient of variation (CV) (CV control 0.27 ± 0.016, CV AM 251 0.15 ± 0.02, n 15, p < 0.02, paired t-test, control vs. AM 251, Figure 1B) and paired-pulse ratio (PPR) of eEPSCs (PPR control 1.31 ± 0.06, PPR AM 251 1.02 ± 0.05, n 12, p < 0.05 paired t-test, control vs. AM 251, Figure 1C), which resulted in a leftward shift of the cumulative distribution of PPR (n 16, Kolmogorov-Smirnov test, p < 0.01, Figure 1D)
Summary
Neurons dynamically regulate the strength of their synaptic inputs by adjusting the parameters of synaptic transmission using various signaling molecules, including endocannabinoids (eCBs), a family of neuroactive lipids (Castillo et al, 2012). Tonic Endocannabinoid Signaling in Dorsal Raphe Nucleus synthesized and released “on demand” from postsynaptic neurons in response to phasic neuronal activation (Kreitzer and Regehr., 2001; Ohno-Shosaku et al, 2001; Wilson and Nicoll, 2001), and/or stimulation of Gq/11-coupled neurotransmitter receptors (Haj-Dahmane and Shen, 2005; Hashimotodani et al, 2005; Maejima et al, 2005) This phasic eCB signaling mediates retrograde modulation of synaptic transmission and plasticity throughout the central nervous system via presynaptic cannabinoid 1 receptors (CB1Rs) (Castillo et al, 2012; Ohno-Shosaku and Kano, 2014). Through retrograde and autocrine signaling, phasic eCB release regulates neuronal excitability and gates various forms of synaptic plasticity in the brain (Araque et al, 2017)
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