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

Abstract

Synaptic efficacy changes, long-term potentiation (LTP) and depression (LTD), underlie various forms of learning and memory. Synaptic plasticity is generally assessed under prolonged activation, whereas learning can emerge from few or even a single trial. Here, we investigated the existence of rapid responsiveness of synaptic plasticity in response to a few number of spikes, in neocortex in a synaptic Hebbian learning rule, the spike-timing-dependent plasticity (STDP). We investigated the effect of lowering the number of pairings from 100 to 50, and 10 on STDP expression, using whole-cell recordings from pyramidal cells in rodent somatosensory cortical brain slices. We found that a low number of paired stimulations induces LTP at neocortical layer 4–2/3 synapses. Besides the asymmetric Hebbian STDP reported in the neocortex induced by 100 pairings, we observed a symmetric anti-Hebbian LTD for 50 pairings and unveiled a unidirectional Hebbian spike-timing-dependent LTP (tLTP) induced by 10–15 pairings. This tLTP was not mediated by NMDA receptor activation but requires CB1 receptors and transient receptor potential vanilloid type-1 (TRPV1) activated by endocannabinoids (eCBs). eCBs have been widely described as mediating short- and long-term synaptic depression. Here, the eCB-tLTP reported at neocortical synapses could constitute a substrate operating in the online learning of new associative memories or during the initial stages of learning. In addition, these findings should provide useful insight into the mechanisms underlying eCB-plasticity occurring during marijuana intoxication.

Dopamine–endocannabinoid interactions mediate spike-timing-dependent potentiation in the striatum

“…This view is now challenged by studies reporting opposite effects (potentiation) in various brain structures using various signaling pathways 3 – 13 . We describe here and in previous studies 11 – 13 , 50 a tLTP in mammals, wherein eCB signaling directly underlies both the induction and the long-term maintenance of synaptic weight increase.…”

“…Indeed, eCBs promote long-term potentiation (LTP) at mixed (chemical and electrical) synapses of the goldfish Mauthner cell via intermediary dopaminergic neurons 3 or at hippocampal CA1 synapses via a GABA A receptor-mediated mechanism 4 – 6 , facilitation of hippocampal LTP via eCB-induced presynaptic depression of GABAergic transmission 7 , and heterosynaptic short-term potentiation via the astrocytic network 8 . Recently, a direct role of eCBs has been found in promoting LTP in the dentate gyrus 9 , 10 , the somatosensory cortex 11 , and the dorsolateral striatum 12 , 13 .…”

Lights on Endocannabinoid-Mediated Synaptic Potentiation

“…Using spike-timing-dependent plasticity (STDP), a Hebbian synaptic learning rule relying on paired activity on either side of the synapses (Feldman, 2012), a few numbers of pairings induce eCB-LTP at corticostriatal synapses, which is CB 1 R-and TRPV1-mediated (Cui et al, 2015(Cui et al, , 2016(Cui et al, , 2018aXu et al, 2018; Figure 1A). 2-AG levels and subsequent CB 1 R activation have a dual effect on eCB-plasticity: high levels of eCBs synthesis and CB 1 R activation (reached with ∼10-15 post-pre pairings) induce eCB-LTP, while low levels (reached with ∼50-100 pre-post pairings) induce eCB-LTD (Cui et al, 2015(Cui et al, , 2016.…”

“…Therefore, at corticostriatal synapses, eCB-mediated plasticity is bidirectional, and eCB-LTP or eCB-LTD expression is determined by pre-and postsynaptic activity patterns. A similar form of homosynaptic and bidirectional eCB-plasticity occurs between neocortical pyramidal cells following a limited number of coincident activity (Cui et al, 2018b). Interestingly, eCB-LTP is robust to spike-time jittering, contrarily to NMDAR-LTP, and can thus arise in noisy neural network activity (Cui et al, 2018a).…”

Engrams of Fast Learning

“…Interestingly, LTP magnitude is not affected by adding more pairings, suggesting a potentially rapid memory acquisition through the induction of an abrupt all-or-none LTP in response to minimal stimulation, as observed at CA3-CA1 synapses (Petersen et al, 1998). Moreover, in striatal projecting neurons and in L5 pyramidal cells of the somatosensory cortex, in vitro STDP paradigms involving ∼5-15 cortico-striatal pairings induce an endocannabinoid-mediated LTP (eCB-LTP; Cui et al, 2015Cui et al, , 2016Cui et al, , 2018aXu et al, 2018;Gangarossa et al, 2020; Figure 1G). This LTP disappears for 25-50 pairings, only to re-emerge at 75 pairings as an NMDAR-mediated LTP (NMDAR-LTP).…”