The dorsolateral striatum (DLS) of the basal ganglia plays a critical role in action selection and motor control. The DLS receives cortical and thalamic afferents, which are extensively modulated by monoaminergic inputs, such as dopamine and serotonin (5-HT). Dopamine and 5-HT act as circuit neuromodulators by activating both stimulatory (Gs) and inhibitory (Gi) protein-coupled receptors that regulate synaptic mechanisms of plasticity.
On a system level, 5-HT signal has been classically associated with learning of negative events, acting as an opponent of dopamine regulation of rewarding processes. Recent evidence has challenged this view, suggesting that 5HT 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.
To address this hypothesis, we investigated the role of serotonergic signaling in regulating the strength of glutamatergic synaptic connections to the Medium Spiny Neurons of the direct pathway (dMSNs), which mediate movement, reward and reinforcement. Specifically, we focused on the regulation of distinct forms of long-term synaptic plasticity that depend on both the relative timing of a neuron output and an input spike (Spike timing-dependent plasticity, STDP), and on the pattern of neuronal stimulation (high-frequency stimulation, HFS). Upon a STDP protocol, the chemo-genetic inhibition of 5-HT release resulted in a long lasting depression (STDP-LTD) of glutamatergic afferents to the dMSNs of the DLS. The synaptic effects of chemo-genetic inhibition of 5-HT release were recapitulated by the pharmacological inhibition of the Gs-coupled 5-HT4 receptor subtype (5-HT4R).
This form of LTD was independent from presynaptic CB1 receptor (CB1R) activation, it showed a postsynaptic locus of expression, and it was associated with an increased dendritic Ca2+ signal. We obtained similar results upon HFS; antagonism of 5-HT4R resulted in a CB1R independent form of HFS-LTD, which was associated with enhanced dendritic Ca2+ levels.
Collectively, these data provide molecular and synaptic insights on the neuromodulatory role of 5-HT at striatal circuits. Dysfunctional serotonergic modulation of striatal circuits has been associated with repetitive behaviors in obsessive-compulsive disorders (OCD). Thus, elucidating how 5-HT4R manipulation affects aspects of reward-guided behavior, and how this is causally relevant for defined cognitive processes implicated in action control, could facilitate the development of new pharmacological approaches to treat OCD symptoms
