Clarkson Rebecca L, Liptak Alayna T, Gee Steven M, Sohal Vikaas S, Bender Kevin J
Weill Institute for Neuroscience and Center for Integrative Neuroscience.
Graduate Program in Neuroscience.
J Neurosci. 2017 Jun 14;37(24):5846-5860. doi: 10.1523/JNEUROSCI.0310-17.2017. Epub 2017 May 18.
The D3 dopamine receptor, a member of the G-coupled D2 family of dopamine receptors, is expressed throughout limbic circuits affected in neuropsychiatric disorders, including prefrontal cortex (PFC). These receptors are important for prefrontal executive function because pharmacological and genetic manipulations that affect prefrontal D3 receptors alter anxiety, social interaction, and reversal learning. However, the mechanisms by which D3 receptors regulate prefrontal circuits and whether D3 receptors regulate specific prefrontal subnetworks remains unknown. Here, we combine dopamine receptor reporter lines, anatomical tracing techniques, and electrophysiology to show that D3 receptor expression defines a novel subclass of layer 5 glutamatergic pyramidal cell in mouse PFC (either sex). D3-receptor-expressing pyramidal neurons are electrophysiologically and anatomically separable from neighboring neurons expressing D1 or D2 receptors based on their dendritic morphology and subthreshold and suprathreshold intrinsic excitability. D3-receptor-expressing neurons send axonal projections to intratelencephalic (IT) targets, including contralateral cortex, nucleus accumbens, and basolateral amygdala. Within these neurons, D3 receptor activation was found to regulate low-voltage-activated Ca3.2 calcium channels localized to the axon initial segment, which suppressed action potential (AP) excitability, particularly when APs occurred at high frequency. Therefore, these data indicate that D3 receptors regulate the excitability of a unique, IT prefrontal cell population, thereby defining novel circuitry and cellular actions for D3 receptors in PFC. The D3 dopamine receptor, a member of the G-coupled D2 family of dopamine receptors, are expressed throughout limbic circuits, including prefrontal cortex (PFC). They are of broad interest as a site for therapeutic intervention in serious mental illness, yet we know very little about their distribution or function within PFC. Here, we show that D3 receptors define a unique population of glutamatergic principal cells in mouse PFC that largely lack expression of D1 or D2 receptors. Within these cells, we find that D3 receptors regulate the ability to generate high-frequency action potential bursts through mechanisms not supported by other dopamine receptors. These results define unique circuitry and cellular actions for D3 receptors in regulating PFC networks.
D3多巴胺受体是G蛋白偶联多巴胺受体D2家族的成员之一，在包括前额叶皮质（PFC）在内的受神经精神疾病影响的整个边缘回路中均有表达。这些受体对前额叶执行功能很重要，因为影响前额叶D3受体的药理学和基因操作会改变焦虑、社交互动和逆向学习。然而，D3受体调节前额叶回路的机制以及D3受体是否调节特定的前额叶子网仍然未知。在这里，我们结合多巴胺受体报告系、解剖追踪技术和电生理学，表明D3受体表达定义了小鼠PFC（无论雌雄）中第5层谷氨酸能锥体神经元的一个新亚类。基于树突形态以及阈下和阈上内在兴奋性，表达D3受体的锥体神经元在电生理学和解剖学上与表达D1或D2受体的相邻神经元是可分离的。表达D3受体的神经元向脑内（IT）靶点发出轴突投射，包括对侧皮质、伏隔核和基底外侧杏仁核。在这些神经元中，发现D3受体激活可调节定位于轴突起始段的低电压激活Ca3.2钙通道，从而抑制动作电位（AP）兴奋性，尤其是当动作电位高频发生时。因此，这些数据表明D3受体调节独特的IT前额叶细胞群的兴奋性，从而确定了D3受体在PFC中的新回路和细胞作用。D3多巴胺受体是G蛋白偶联多巴胺受体D2家族的成员之一，在包括前额叶皮质（PFC）在内的整个边缘回路中均有表达。作为严重精神疾病治疗干预的靶点，它们备受关注，但我们对其在PFC中的分布或功能知之甚少。在这里，我们表明D3受体定义了小鼠PFC中独特的谷氨酸能主细胞群，这些细胞在很大程度上缺乏D1或D2受体的表达。在这些细胞中，我们发现D3受体通过其他多巴胺受体不支持的机制调节产生高频动作电位爆发的能力。这些结果确定了D3受体在调节PFC网络中的独特回路和细胞作用。
