Abstract
Synaptic plasticity is a cardinal cellular mechanism for learning and memory. The endocannabinoid (eCB) system has emerged as a pivotal pathway for synaptic plasticity because of its widely characterized ability to depress synaptic transmission on short- and long-term scales. Recent reports indicate that eCBs also mediate potentiation of the synapse. However, it is not known how eCB signaling may support bidirectionality. Here, we combined electrophysiology experiments with mathematical modeling to question the mechanisms of eCB bidirectionality in spike-timing dependent plasticity (STDP) at corticostriatal synapses. We demonstrate that STDP outcome is controlled by eCB levels and dynamics: prolonged and moderate levels of eCB lead to eCB-mediated long-term depression (eCB-tLTD) while short and large eCB transients produce eCB-mediated long-term potentiation (eCB-tLTP). Moreover, we show that eCB-tLTD requires active calcineurin whereas eCB-tLTP necessitates the activity of presynaptic PKA. Therefore, just like glutamate or GABA, eCB form a bidirectional system to encode learning and memory.
Highlights
Bidirectional long-term plasticity of synaptic strength (LTD and LTP) underlies multiple forms of learning and memory (Citri and Malenka, 2008; Nabavi et al, 2014)
Examples of tLTP and tLTD induced by 100 post-pre and 100 pre-post pairings are shown in C1 and D1, respectively, and the experiment summary in C2 and D2. tLTP was NMDAR-mediated since blocked by the selective NMDAR blocker D-AP5 (50 mM) (99±3%, p=0.7998, n=4) (Figure 1C2). while tLTD relied on eCBs because pharmacological inhibition of CB1R with AM251 (3 mM) impaired this plasticity (102±7%, p=0.8108, n=4) (Figure 1D2)
As recently reported (Cui et al, 2015), lowering the number of pairings down to 10 yields tLTP for post-pre pairings (163±12%, p
Summary
Bidirectional long-term plasticity of synaptic strength (LTD and LTP) underlies multiple forms of learning and memory (Citri and Malenka, 2008; Nabavi et al, 2014). Endocannabinoids (eCBs) have emerged as a major actor in learning and memory because of their powerful influence on synaptic plasticity (Chevaleyre et al, 2006; Heifets and Castillo, 2009; Kano et al, 2009; Katona and Freund, 2012). The major neurotransmitter systems, glutamate and GABA, allow bidirectional synaptic plasticity (Citri and Malenka, 2008), i.e. the same signaling pathway in the same cell gates the neuron towards potentiation or depression depending on the activity pattern. Recent reports challenge this view and indicate that eCBs could act as a bidirectional system for synaptic plasticity.
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