Associative, bidirectional changes in neural signaling utilizing NMDA receptor- and endocannabinoid-dependent mechanisms

Abstract

Persistent, bidirectional changes in synaptic signaling (that is, potentiation and depression of the synapse) can be induced by the precise timing of individual pre-and postsynaptic action potentials. However, far less attention has been paid to the ability of paired trains of action potentials to elicit persistent potentiation or depression. We examined plasticity following the pairing of spike trains in the touch mechanosensory neuron (T cell) and S interneuron (S cell) in the medicinal leech. Long-term potentiation (LTP) of T to S signaling was elicited when the T-cell spike train preceded the S-cell train. An interval 0 to +1 sec between the T-and S-cell spike trains was required to elicit long-term potentiation (LTP), and this potentiation was NMDA receptor (NMDAR)-dependent. Long-term depression (LTD) was elicited when S-cell activity preceded T-cell activity and the interval between the two spike trains was 20.2 sec to 210 sec. This surprisingly broad temporal window involved two distinct cellular mechanisms; an NMDAR-mediated LTD (NMDAR-LTD) when the pairing interval was relatively brief (,21 sec) and an endocannabinoid-mediated LTD (eCB-LTD) when longer pairing intervals were used (21 to 210 sec). This eCB-LTD also required activation of a presynaptic transient receptor potential vanilloid (TRPV)-like receptor, presynaptic Ca 2+ release from intracellular stores and activation of voltage-gated Ca 2+ channels (VGCCs). These findings demonstrate that the pairing of spike trains elicits timing-dependent forms of LTP and LTD that are supported by a complex set of cellular mechanisms involving NMDARs and endocannabinoid activation of TRPV-like receptors.[Supplemental material is available for this article.]Associative forms of long-term neuroplasticity, as first proposed by Hebb (1949), depend on the temporal relationship between pre-and postsynaptic activity. Studies of spike-timing-dependent plasticity (STDP) have provided experimental confirmation of this principle, specifically that in most connections long-term potentiation (LTP) is produced when a presynaptic action potential (or spike) precedes the postsynaptic spike, whereas long-term depression (LTD) is produced when the order is reversed (see review by Caporale and Dan 2008). In addition to the temporal order being important in determining the sign of the synaptic change, temporal proximity is also critical in that the time between the pre-and postsynaptic activity must be sufficiently brief, usually ,40 msec, to support potentiation or depression.It has been noted that the time intervals between pre-and postsynaptic activity that support STDP are not as long as those observed in many associative learning experiments, in which interstimulus intervals on the scale of seconds can be used to elicit successful conditioning (Drew and Abbott 2006). Most studies of STDP involve pairing single pre-and postsynaptic spikes or brief bursts of two to three spikes; however, many neurons communicate using relatively long trains of action potentials that are tens...

The evolution and comparative neurobiology of endocannabinoid signalling

“…Evidence that presynaptic TRPV-type-receptormediated LTD may be a widespread mechanism of synaptic plasticity in the leech nervous system has been obtained in a subsequent study, using the leech T-S synaptic pathway as a model preparation [128]. LTD is induced when a spike train is triggered in the S cell 1-10 s prior to stimulation of the T cell and this is blocked by perfusion of the preparation with the cannabinoid receptor antagonist AM251 or the DAGL inhibitor RHC80267 and by injection of the DAGL inhibitor tetrahydrolipstatin into the S cell.…”

Physiological and behavioral evidence of a capsaicin sensitive TRPV-like channel in the medicinal leech

“…The endocannabinoids and endovanilloids AEA and 2-AG are present in the leech CNS (Matias et al, 2001), yet the leech and other protostomal invertebrates lack orthologs to the CB1 and CB2 receptors (Elphick, 2012). There is, however, evidence that central TRPV-like channels mediate synaptic plasticity in the leech via mechanisms that are similar to those observed in vertebrates (Li and Burrell, 2010;Yuan and Burrell, 2010;Li and Burrell, 2011;Yuan and Burrell, 2012; Higgins et al, 2013;Yuan and Burrell, 2013). …”

Seasonal variation of long-term potentiation at a central synapse in the medicinal leech

“…It is not clear whether this variation is due to differences intrinsic to the different synapses, differences in the stimulation protocols used to induce LTP/LTD, or both. Our studies in other synapses used either tetanic stimulation or low frequency stimulation to induce LTP and LTD, respectively (Burrell and Sahley, 2004;Burrell and Li, 2008;Li and Burrell, 2009;Yuan and Burrell, 2010), or used more pairings of presynaptic and postsynaptic activity than utilized in the current study [5 in the present study versus 10 pairings in another recent study (Li and Burrell, 2011)]. It is possible that these other studies stimulated the synapses in a strong enough manner to overcome any seasonal influences on LTP or LTD.…”