Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

Abstract

Endocannabinoids (ECBs) depress transmitter release at sites throughout the brain. Here, we describe another form of ECB signaling that triggers a novel form of long-term potentiation (LTP) localized to the lateral perforant path (LPP) which conveys semantic information from cortex to hippocampus. Two cannabinoid CB 1 receptor (CB 1 R) signaling cascades were identified in hippocampus. The first is pregnenolone sensitive, targets vesicular protein Munc18-1 and depresses transmitter release; this cascade is engaged by CB 1 Rs in Schaffer-Commissural afferents to CA1 but not in the LPP, and it does not contribute to LTP. The second cascade is pregnenolone insensitive and LPP specific; it entails co-operative CB 1 R/β1-integrin signaling to effect synaptic potentiation via stable enhancement of transmitter release. The latter cascade is engaged during LPP-dependent learning. These results link atypical ECB signaling to the encoding of a fundamental component of episodic memory and suggest a novel route whereby endogenous and exogenous cannabinoids affect cognition.

Endocannabinoid-LTP Mediated by CB1 and TRPV1 Receptors Encodes for Limited Occurrences of Coincident Activity in Neocortex

“…This tLTP was not NMDAR-dependent but eCB-mediated and required the activation of CB 1 receptors and transient receptor potential vanilloid type-1 (TRPV1). Our study evidences, together with recent reports (Cui et al, 2015 , 2016 ; Wang et al, 2016 , 2018 ; Maglio et al, 2018 ) that eCB system not only promotes LTD but also LTP. Therefore, endocannabinoids (eCBs) can underlie bidirectional plasticity, depending on the regime of activity pattern on both sides of the synapse.…”

“…It has also been reported in the hippocampus that eCB-induced presynaptic depression of GABAergic transmission facilitates LTP (Carlson et al, 2002 ; Chevaleyre and Castillo, 2004 ; Zhu and Lovinger, 2007 ), or that eCBs mediate heterosynaptic short-term potentiation via intermediary astrocytes (Navarrete and Araque, 2010 ). More recently, it has been reported a direct role of eCBs in promoting LTP at cortical inputs to the granule cells of the dentate gyrus (Wang et al, 2016 , 2018 ), to the medium-sized spiny neurons of the dorsolateral striatum (Cui et al, 2015 , 2016 ) or to the basal dendrites of layer 5 pyramidal cells (in this later case the eCB-LTP is also BDNF- and NMDAR-mediated; Maglio et al, 2018 ). At hippocampal CA1 synapses, eCB-mediated LTP induced with high-frequency (Lin et al, 2011 ), low-frequency (Zhu and Lovinger, 2007 ) or paired (Xu et al, 2012 ) stimulations were prevented by inhibition of CB 1 R and GABA A receptors.…”

Inhibitor of Endocannabinoid Deactivation Protects Against In Vitro and In Vivo Neurotoxic Effects of Paraoxon

“…Noting that neuronal stimulation activates β1 integrins in hippocampal synapses (Babayan et al 2012), the excitatory over-activation through Pxn toxicity may be initiating a level of synaptic cofilin and other signaling above that which maintains physiological neurotransmission and plasticity (see Woo et al 2015;Lauterborn et al 2017). Of the two cannabinoid CB1 receptor (CB1R) signaling cascades recently identified (Wang et al 2017), perhaps the protective endocannabinoid action of AM5206 occurs through the cascade that is independent of cooperative CBR1/β1 integrin responses.…”

Cannabinoid Modulation of the Stressed Hippocampus

“…Additionally, Chávez et al ( 2010 ) have shown that AEA induces LTD in the dentate gyrus in a TRPV1 receptor-dependent manner. Wang W. et al ( 2017 ) showed that the activation of CB 1 receptors modulates the synaptic responses of hippocampal pathways in different ways. In the Schaffer Commissural pathway, CB 1 activation decreased excitatory post-synaptic potential and impaired LTP induction via an ERK1/2-MUNC18-1-dependent neurotransmitter release.…”