Dopamine D1 receptor signaling and endocannabinoid cooperate to fuel striatal plasticity

Endocannabinoids (eCBs) play key roles in short‐term and long‐term synaptic plasticity in the corticostriatal circuit. By activating cannabinoid receptors expressed in the central nervous system, eCBs regulate several neural functions and behaviors. The major eCB 2‐arachidonoyl‐glycerol (2‐AG) is particularly important for triggering a short‐term form of synaptic plasticity (depolarization‐induced suppression of excitatory transmission or DSE) on cortical glutamatergic afferents inputting the striatum. The neurotransmitter dopamine, through the action of D1 and D2 receptors, is also critically involved in corticostriatal plasticity. This Editorial highlights the study by Shonesy et al., which presents evidence that activation of dopamine D1 receptor and its classical downstream target cAMP‐dependent protein kinase (PKA) are involved in increasing the synthesis of 2‐AG in striatal medium spiny neurons (MSN) to drive DSE in the corticostriatal circuit, as schematically outlined in Figure 1. The authors used a set of complementary approaches and identified a putative serine (Ser) residue phosphorylated by PKA in diacylglycerol lipase (DGL) alpha that is required for generating 2‐AG, providing a mechanistic clue into how the canonical D1 pathway in MSN might fine‐tune short‐term plasticity in the corticostriatal circuit. Besides, the work by Shonesy et al. may pave the way for further studies exploring the signaling interplay between canonical dopamine D1 receptor pathway and eCBs to control other forms of synaptic plasticity in different brain circuits with possible pathological relevance.