Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
J Neurosci. 2011 Jan 5;31(1):142-56. doi: 10.1523/JNEUROSCI.1970-10.2011.
Schizophrenia may involve hypofunction of NMDA receptor (NMDAR)-mediated signaling, and alterations in parvalbumin-positive fast-spiking (FS) GABA neurons that may cause abnormal gamma oscillations. It was recently hypothesized that prefrontal cortex (PFC) FS neuron activity is highly dependent on NMDAR activation and that, consequently, FS neuron dysfunction in schizophrenia is secondary to NMDAR hypofunction. However, NMDARs are abundant in synapses onto PFC pyramidal neurons; thus, a key question is whether FS neuron or pyramidal cell activation is more dependent on NMDARs. We examined the AMPAR and NMDAR contribution to synaptic activation of FS neurons and pyramidal cells in the PFC of adult mice. In FS neurons, EPSCs had fast decay and weak NMDAR contribution, whereas in pyramidal cells, EPSCs were significantly prolonged by NMDAR-mediated currents. Moreover, the AMPAR/NMDAR EPSC ratio was higher in FS cells. NMDAR antagonists decreased EPSPs and EPSP-spike coupling more strongly in pyramidal cells than in FS neurons, showing that FS neuron activation is less NMDAR dependent than pyramidal cell excitation. The precise EPSP-spike coupling produced by fast-decaying EPSCs in FS cells may be important for network mechanisms of gamma oscillations based on feedback inhibition. To test this possibility, we used simulations in a computational network of reciprocally connected FS neurons and pyramidal cells and found that brief AMPAR-mediated FS neuron activation is crucial to synchronize, via feedback inhibition, pyramidal cells in the gamma frequency band. Our results raise interesting questions about the mechanisms that might link NMDAR hypofunction to alterations of FS neurons in schizophrenia.
精神分裂症可能涉及 NMDA 受体 (NMDAR) 介导的信号转导功能低下，以及 GABA 能中间神经元中 Parvalbumin 阳性的快速放电 (FS) 神经元的改变，这些改变可能导致异常的伽马振荡。最近有人假设，前额叶皮层 (PFC) FS 神经元的活动高度依赖于 NMDAR 的激活，因此，精神分裂症中 FS 神经元功能障碍是 NMDAR 功能低下的结果。然而，NMDAR 在 PFC 锥体神经元的突触中含量丰富；因此，一个关键问题是 FS 神经元或锥体细胞的激活是否更依赖于 NMDAR。我们研究了 AMPAR 和 NMDAR 对成年小鼠 PFC 中 FS 神经元和锥体细胞突触激活的贡献。在 FS 神经元中，EPSC 衰减迅速，NMDAR 贡献较弱，而在锥体细胞中，NMDAR 介导的电流使 EPSC 显著延长。此外，FS 细胞中的 AMPAR/NMDAR EPSC 比值较高。NMDA 受体拮抗剂在锥体细胞中比在 FS 神经元中更强烈地降低 EPSPs 和 EPSP-棘波偶联，表明 FS 神经元的激活比锥体细胞的兴奋对 NMDAR 的依赖性更小。快速衰减的 EPSC 在 FS 细胞中产生的精确 EPSP-棘波偶联对于基于反馈抑制的伽马振荡的网络机制可能很重要。为了验证这一可能性，我们在一个相互连接的 FS 神经元和锥体细胞的计算网络中进行了模拟，发现短暂的 AMPAR 介导的 FS 神经元激活对于通过反馈抑制使锥体细胞在伽马频带中同步是至关重要的。我们的结果提出了一些有趣的问题，即哪些机制可能将 NMDAR 功能低下与精神分裂症中 FS 神经元的改变联系起来。
