Departments of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Departments of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Neurobiol Dis. 2014 Mar;63:129-40. doi: 10.1016/j.nbd.2013.11.021. Epub 2013 Dec 8.
Microdeletion of the human CHRNA7 gene (α7 nicotinic acetylcholine receptor, nAChR) as well as dysfunction in N-methyl-d-aspartate receptors (NMDARs) have been associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia. However, the pathophysiological roles of synaptic vs. extrasynaptic NMDARs and their interactions with α7 nAChRs in cortical dysfunction remain largely uncharacterized. Using a combination of in vivo and in vitro models, we demonstrate that α7 nAChR gene deletion leads to specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in mouse cortex. α7 nAChR null mice had decreased cortical NMDAR expression and glutamatergic synapse formation during postnatal development. Similar reductions in NMDAR expression and glutamatergic synapse formation were revealed in cortical cultures lacking α7 nAChRs. Interestingly, synaptic, but not extrasynaptic, NMDAR currents were specifically diminished in cultured cortical pyramidal neurons as well as in acute prefrontal cortical slices of α7 nAChR null mice. Moreover, d-serine responsive synaptic NMDAR-mediated currents and levels of the d-serine synthetic enzyme serine racemase were both reduced in α7 nAChR null cortical pyramidal neurons. Our findings thus identify specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in α7 nAChR gene deletion models of cortical dysfunction, thereby implicating α7 nAChR-mediated control of synaptic NMDARs and serine racemase/d-serine pathways in cortical dysfunction underlying many neuropsychiatric and neurodevelopmental disorders, particularly those associated with deletion of human CHRNA7.
人类 CHRNA7 基因（α7 烟碱型乙酰胆碱受体，nAChR）的微缺失以及 N-甲基-D-天冬氨酸受体（NMDAR）功能障碍与广泛的神经发育和神经精神疾病中的皮质功能障碍有关，包括精神分裂症。然而，突触与 extrasynaptic NMDARs 的病理生理作用及其与α7 nAChR 在皮质功能障碍中的相互作用在很大程度上仍未得到描述。我们使用体内和体外模型的组合证明，α7 nAChR 基因缺失导致突触 NMDAR 及其共激动剂 d-丝氨酸以及谷氨酸能突触缺陷的特异性丧失在小鼠皮质中。α7 nAChR 缺失小鼠在出生后发育过程中皮质 NMDAR 表达和谷氨酸能突触形成减少。在缺乏α7 nAChR 的皮质培养物中也揭示了类似的 NMDAR 表达和谷氨酸能突触形成减少。有趣的是，在培养的皮质锥体神经元以及α7 nAChR 缺失小鼠的急性前额皮质切片中，仅突触而非 extrasynaptic NMDAR 电流特异性减少。此外，在α7 nAChR 缺失的皮质锥体神经元中，d-丝氨酸反应性突触 NMDAR 介导的电流和 d-丝氨酸合成酶丝氨酸 racemase 的水平均降低。我们的研究结果因此确定了在皮质功能障碍的α7 nAChR 基因缺失模型中突触 NMDAR 及其共激动剂 d-丝氨酸以及谷氨酸能突触缺陷的特异性丧失，从而表明α7 nAChR 介导的突触 NMDAR 控制和丝氨酸 racemase/d-丝氨酸途径在许多神经精神和神经发育障碍中的皮质功能障碍，特别是与人类 CHRNA7 缺失相关的那些。
