Excitatory serotonergic signaling regulates synaptic plasticity at striatal glutamatergic inputs

The dorsal striatum receives glutamatergic cortical and thalamic afferents, which are extensively modulated by monoaminergic inputs, such as dopamine and serotonin (5-HT). Various models have been proposed regarding the interactions between reward and punishment, with serotonin closely associated with learning of negative events, and countervailing dopamine regulation of corticostriatal circuits and reward. Recent evidence has challenged this view, suggesting that 5-HT signaling can synergize with dopamine signaling to shape reward-guided behavior. However, the molecular and synaptic correlates of this behavioral role of 5-HT at striatal circuits remain to be established. In the dorsolateral striatum, we found that the chemogenetic inhibition of 5-HT release resulted in a spike-timing-dependent form of long-term depression (t-LTD) at glutamatergic synapses on striatal projection neurons of the direct pathway (dSPNs). These synaptic effects of chemogenetic inhibition of 5-HT release were recapitulated by the pharmacological inhibition of the Gs-coupled 5-HT4 receptor subtype (5-HT4R). t-LTD is independent from endocannabinoid signaling, shows a postsynaptic locus of expression, and it is associated with an increased dendritic Ca2+ signal. Additionally, optogenetic interrogation of glutamatergic inputs to dSPNs indicated that this form of t-LTD is expressed at thalamostriatal synapses. Inhibiting in-vivo 5-HT4R during instrumental conditioning of nose-poke for food reward affected goal-directed control of behavior, thus supporting the role of striatal 5-HT signaling in mediating aspects of reward-guided behavior.