The principal neurons of the striatum, the spiny projection neurons (SPNs), make inhibitory synaptic connections with each other via collaterals of their main axon, forming a local lateral inhibition network. Serotonin, acting via the 5-HT1B receptor, modulates neurotransmitter release from SPN terminals in striatal output nuclei, but the role of 5-HT1B receptors in lateral inhibition among SPNs in the striatum is unknown. Here, we report the effects of 5-HT1B receptor activation on lateral inhibition in the mouse striatum. Whole-cell recordings were made from SPNs in acute brain slices of either sex, while optogenetically activating presynaptic SPNs or fast-spiking interneurons (FSIs). Activation of 5-HT1B receptors significantly reduced the amplitude of IPSCs evoked by optical stimulation of both direct and indirect pathway SPNs. This reduction was blocked by application of a 5-HT1B receptor antagonist. Activation of 5-HT1B receptors did not reduce the amplitude of IPSCs evoked from FSIs. These results suggest a new role for serotonin as a modulator of lateral inhibition among striatal SPNs. The 5-HT1B receptor may, therefore, be a suitable target for future behavioral experiments investigating the currently unknown role of lateral inhibition in the function of the striatum.

SIGNIFICANCE STATEMENT We show that stimulation of serotonin receptors reduces the efficacy of lateral inhibition between spiny projection neurons (SPNs), one of the biggest GABAergic sources in the striatum, by activation of the serotonin 5-HT1B receptor. The striatum receives serotonergic input from the dorsal raphe nuclei and is important in behavioral brain functions like learning and action selection. Our findings suggest a new role for serotonin in modulating the dynamics of neural interactions in the striatum, which extends current knowledge of the mechanisms of the behavioral effects of serotonin.

纹状体的主要神经元，即多刺投射神经元 (SPNs)，通过其主要轴突的侧枝相互建立抑制性突触连接，形成局部侧抑制网络。血清素通过 5-HT1B 受体作用，调节纹状体输出核中 SPN 末端的神经递质释放，但 5-HT1B 受体在纹状体中 SPN 的侧向抑制中的作用尚不清楚。在这里，我们报告了 5-HT1B 受体激活对小鼠纹状体侧向抑制的影响。全细胞记录由任一性别的急性脑切片中的 SPN 制成，同时光遗传学激活突触前 SPN 或快速尖峰中间神经元 (FSI)。5-HT1B 受体的激活显着降低了由直接和间接途径 SPN 的光刺激引起的 IPSC 的振幅。这种减少被 5-HT1B 受体拮抗剂的应用所阻止。5-HT1B 受体的激活不会降低由 FSI 引起的 IPSC 的振幅。这些结果表明血清素作为纹状体 SPN 中侧抑制调节剂的新作用。因此，5-HT1B 受体可能是未来行为实验的合适靶标，研究目前未知的侧抑制在纹状体功能中的作用。

意义声明我们表明，通过激活血清素 5-HT1B 受体，血清素受体的刺激会降低多刺投射神经元 (SPN)（纹状体中最大的 GABA 能来源之一）之间的侧向抑制的功效。纹状体接收来自中缝背核的血清素输入，并且在学习和行动选择等行为大脑功能中很重要。我们的研究结果表明，血清素在调节纹状体神经相互作用动力学方面发挥了新作用，这扩展了目前对血清素行为影响机制的认识。