Neuroscience Graduate Program, University of Southern California, Los Angeles, California 90089.
Neuroscience Graduate Program, University of Southern California, Los Angeles, California 90089
J Neurosci. 2023 Dec 6;43(49):8336-8347. doi: 10.1523/JNEUROSCI.0185-23.2023.
Many glutamatergic synapse proteins contain a 4.1N protein binding domain. However, a role for 4.1N in the regulation of glutamatergic neurotransmission has been controversial. Here, we observe significantly higher expression of protein 4.1N in granule neurons of the dentate gyrus (DG granule neurons) compared with other hippocampal regions. We discover that reducing 4.1N expression in rat DG granule neurons of either sex results in a significant reduction in glutamatergic synapse function that is caused by a decrease in the number of glutamatergic synapses. By contrast, we find reduction of 4.1N expression in hippocampal CA1 pyramidal neurons has no impact on basal glutamatergic neurotransmission. We also find 4.1N's C-terminal domain (CTD) to be nonessential to its role in the regulation of glutamatergic synapses of DG granule neurons. Instead, we show that 4.1N's four-point-one, ezrin, radixin, and moesin (FERM) domain is essential for supporting synaptic AMPA receptor (AMPAR) function in these neurons. Altogether, this work demonstrates a novel, cell type-specific role for protein 4.1N in governing glutamatergic synapse function. Glutamatergic synapses exhibit immense molecular diversity. In comparison to heavily studied Schaffer collateral, CA1 glutamatergic synapses, significantly less is known about perforant path-dentate gyrus (DG) synapses. Our data demonstrate that compromising 4.1N function in CA1 pyramidal neurons produces no alteration in basal glutamatergic synaptic transmission. However, in DG granule neurons, compromising 4.1N function leads to a significant decrease in the strength of glutamatergic neurotransmission at perforant pathway synapses. Together, our data identifies 4.1N as a cell type-specific regulator of synaptic transmission within the hippocampus and reveals a unique molecular program that governs perforant pathway synapse function.
许多谷氨酸能突触蛋白含有一个 4.1N 蛋白结合域。然而，4.1N 在调节谷氨酸能神经传递中的作用一直存在争议。在这里，我们观察到在齿状回（DG 颗粒神经元）的颗粒神经元中，蛋白 4.1N 的表达明显高于其他海马区域。我们发现，无论性别如何，减少大鼠 DG 颗粒神经元中 4.1N 的表达都会导致谷氨酸能突触功能显著降低，这是由于谷氨酸能突触数量减少所致。相比之下，我们发现减少海马 CA1 锥体神经元中 4.1N 的表达对基础谷氨酸能神经传递没有影响。我们还发现 4.1N 的 C 端结构域（CTD）对其调节 DG 颗粒神经元谷氨酸能突触的作用不是必需的。相反，我们表明 4.1N 的四个结构域（FERM）结构域对于支持这些神经元中的突触 AMPA 受体（AMPAR）功能是必需的。总之，这项工作表明蛋白 4.1N 在调节谷氨酸能突触功能方面具有新的、细胞类型特异性的作用。谷氨酸能突触表现出巨大的分子多样性。与研究较多的 Schaffer 侧支相比，CA1 谷氨酸能突触，关于穿通路径-齿状回（DG）突触的了解要少得多。我们的数据表明，在 CA1 锥体神经元中削弱 4.1N 功能不会改变基础谷氨酸能突触传递。然而，在 DG 颗粒神经元中，削弱 4.1N 功能会导致穿通路径突触处谷氨酸能神经传递强度显著降低。总之，我们的数据将 4.1N 确定为海马体内突触传递的细胞类型特异性调节剂，并揭示了一个独特的分子程序，该程序控制着穿通路径突触的功能。
