Serotonergic Signaling Controls Input-Specific Synaptic Plasticity at Striatal Circuits

Abstract

Monoaminergic modulation of cortical and thalamic inputs to the dorsal striatum (DS) is crucial for reward-based learning and action control. While dopamine has been extensively investigated in this context, the synaptic effects of serotonin (5-HT) have been largely unexplored. Here, we investigated how serotonergic signaling affects associative plasticity at glutamatergic synapses on the striatal projection neurons of the direct pathway (dSPNs). Combining chemogenetic and optogenetic approaches reveals that impeding serotonergic signaling preferentially gates spike-timing-dependent long-term depression (t-LTD) at thalamostriatal synapses. This t-LTD requires dampened activity of the 5-HT4 receptor subtype, which we demonstrate controls dendritic Ca signals by regulating BK channel activity, and which preferentially localizes at the dendritic shaft. The synaptic effects of 5-HT signaling at thalamostriatal inputs provide insights into how changes in serotonergic levels associated with behavioral states or pathology affect striatal-dependent processes.

Serotonin 5-HT4 receptor boosts functional maturation of dendritic spines via RhoA-dependent control of F-actin

“…5-HT 4 R were shown to modulate several types of K + -channels 22,63 that leads to a longlasting increase in neuronal excitability, and a previous study in adult rats showed that activation of 5-HT 4 R converted weak synaptic potentiation into persistent LTP in the CA1 area 64 . It has also been shown that 5-HT 4 R activation could prevent the learning-induced facilitation of LTD 65,66 and depotentiation of LTP, in both CA1 and dentate gyrus 67 , while regulating LTD in other brain regions through the modulation of the postsynaptic BK channels 22 . Thus, electrophysiology has suggested that, in addition to the synaptic plasticity effects revealed by the molecular biology exploration, 5-HT 4 activation might also affect cell and/or network excitability.…”

“…We have previously shown that the 5-HT 4 R is coupled to the heterotrimeric G13 protein, which in turn selectively activates the small GTPase RhoA 21 . Recently, post-synaptically expressed 5-HT 4 Rs have been found to gate long-term plasticity of excitatory synapses through a local Ca 2+ -dependent mechanism 22 . This finding has provided initial clues to the long-reported effects of 5-HT 4 R activation on learning, memory, and behavior [23][24][25] , including pathological changes associated with neurodegeneration 26 .…”

Transient and sustained effects of dopamine and serotonin signaling in motivation‐related behavior

“…Notably, the same presynaptic action of 5‐HT 1B receptor was transient in PFC inputs, indicating that the same receptor controls transient and sustained mechanisms differentially depending on the respective brain regions. In the postsynapse of SPN in the NAc, the 5‐HT 4 receptor inhibits LTD when coupled with repeated stimulation with glutamate and action potentials . In the neocortex, the transient activation of serotonin facilitated LTD in a 5‐HT 2C receptor‐dependent manner …”

“…In the postsynapse of SPN in the NAc, the 5-HT 4 receptor inhibits LTD when coupled with repeated stimulation with glutamate and action potentials. 92 In the neocortex, the transient activation of serotonin facilitated LTD in a 5-HT 2C receptor-dependent manner. 93 While behavioral studies have shown that dopamine and serotonin modulate learning and stress responses, whether these neurotransmitters share synaptic and cellular mechanisms has not been well reported.…”

Deletion of autism risk gene Shank3 disrupts prefrontal connectivity

“…A micro drill (Cellpoint Scientific Inc.) was used to drill holes through the skull. RV injections were carried out as previously described in adult (12-16-weeks-old) male Shank3B −/− and control Shank3B +/+ littermates (Cavaccini et al, 2018). Injections were performed with a Nanofil syringe mounted on an UltraMicroPump UMP3 with a four channel Micro4 controller (World Precision Instruments), at a speed of 5 nl per seconds, followed by a 5-10 minutes waiting period, to avoid backflow of viral solution and unspecific labelling.…”