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

Abstract

Dopamine modulates striatal synaptic plasticity, a key substrate for action selection and procedural learning. Thus, characterizing the repertoire of activity-dependent plasticity in striatum and its dependence on dopamine is of crucial importance. We recently unraveled a striatal spike-timing-dependent long-term potentiation (tLTP) mediated by endocannabinoids (eCBs) and induced with few spikes (~5–15). Whether this eCB-tLTP interacts with the dopaminergic system remains to be investigated. Here, we report that eCB-tLTP is impaired in a rodent model of Parkinson’s disease and rescued by L-DOPA. Dopamine controls eCB-tLTP via dopamine type-2 receptors (D2R) located presynaptically in cortical terminals. Dopamine–endocannabinoid interactions via D2R are required for the emergence of tLTP in response to few coincident pre- and post-synaptic spikes and control eCB-plasticity by modulating the long-term potentiation (LTP)/depression (LTD) thresholds. While usually considered as a depressing synaptic function, our results show that eCBs in the presence of dopamine constitute a versatile system underlying bidirectional plasticity implicated in basal ganglia pathophysiology.

BDNF controls bidirectional endocannabinoid-plasticity at corticostriatal synapses

“…We investigated the involvement of TrkB activation in bidirectional eCB-plasticity induced by three distinct Hebbian activity patterns: (i) the eCB-LTD induced by a low frequency stimulation (LFS) protocol (600 cortical stimulations at 1 Hz) (Fino et al, 2005; Puente et al, 2011), (ii) the eCB-tLTD induced with 100 STDP pairings (Shen et al, 2008;Fino et al, 2010;Paillé et al, 2013;Cui et al, 2015) and (iii) the eCB-tLTP induced by low numbers of STDP pairings (i.e. ~10) (Cui et al, 2015;Cui et al, 2016;Cui et al, 2018;Xu et al, 2018). To do so, we performed whole-cell recordings from MSNs of the dorsolateral striatum in horizontal brain slices (in which stimulations were performed in the layer 5 of the somatosensory cortex) at postnatal days P25-35 ( Fig.…”

“…5A). Our model is based on the NMDAR-and CB1R-signaling pathways involved in corticostriatal STDP (Pawlak and Kerr, 2008;Shen et al, 2008;Fino et al, 2010;Paillé et al, 2013;Cui et al, 2015) and actually extends to TrkB signaling the mathematical model we validated in previous studies (Cui et al, 2016;Cui et al, 2018;Xu et al, 2018). It expresses the kinetics of the enzymes and binding reactions implicated, including the effects of AMPAR, NMDAR, VSCC and TRPV1, on cytosolic Ca 2+ , IP3-controled Ca 2+ -induced Ca 2+ release from the endoplasmic reticulum, the synthesis of endocannabinoids (2-AG and AEA) via DAG lipase α and FAAH pathways, respectively, and the retrograde activation of presynaptic CB1R (Fig.…”

“…We have previously reported that low numbers of STDP pairings (~10) induce an eCB-tLTP, a form of plasticity dependent on the activation of CB1R at corticostriatal synapses in the dorsolateral striatum (Cui et al, 2015;Cui et al, 2016;Cui et al, 2018;Xu et al, 2018). We thus tested whether the involvement of TrkB was crucial not only in eCB-mediated depression (LFS-eCB-LTD and eCB-tLTD) but also in eCB-tLTP.…”

“…pre-post pairings), repeated n times at 1 Hz. eCB-tLTD was induced with 100 pre-post pairings with 10<ΔtSTDP<20 ms and eCB-tLTP was induced with 10 post-pre pairings with -20<ΔtSTDP<-10 ms as previously described (Cui et al, 2015;Cui et al, 2016;Xu et al, 2018). Recordings were made over a period of 10 minutes at baseline, and for at least 40 minutes after the STDP induction protocols; long-term changes in synaptic efficacy were measured for the last 10 minutes.…”

“…Here, we took advantage of various forms of activity-dependent eCB-plasticity at corticostriatal synapses to investigate the role of BDNF/TrkB signaling in these plasticities. Indeed, in the dorsal striatum, at least three forms of eCB-plasticity have been observed: (i) an eCB-LTD induced by a low frequency stimulation (LFS) (Fino et al, 2005;Puente et al, 2011), (ii) an eCB-LTD induced by 100-150 spiketiming-dependent plasticity (STDP) (eCB-tLTD) (Pawlak and Kerr, 2008;Shen et al, 2008;Fino et al, 2010;Paillé et al, 2013), and (iii) a eCB-tLTP induced by low numbers (~10-15) of STDP pairings (Cui et al, 2015;Cui et al, 2016;Cui et al, 2018;Xu et al, 2018).…”