GluN2D-mediated excitatory drive onto medial prefrontal cortical PV plus fast-spiking inhibitory interneurons
GluN2D-mediated excitatory drive onto medial prefrontal cortical PV plus fast-spiking inhibitory interneurons
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DOI：
10.1371/journal.pone.0233895
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发表时间：
2020-06-04
期刊：
影响因子：
3.7
通讯作者：
Buhl, Derek L.
中科院分区：
文献类型：
--
作者：
Garst-Orozco, Jonathan;Malik, Ruchi;Buhl, Derek L.
背外侧前额叶皮层（dlPFC）内快速发放抑制性中间神经元（FSIN）的缺陷被假设为与精神分裂症相关的认知障碍的基础。虽然代表少数中间神经元，但这种关键细胞类型协调广泛的神经网络伽马频率振荡，与认知和认知灵活性相关。在这里，我们报告的GluN 2D mRNA的表达选择性地在人死后dlPFC组织的小白蛋白阳性细胞，但不是锥体神经元，很少或没有GluN 2C的表达，在任何一种细胞类型。在急性小鼠mPFC切片中，GluN 2C/D选择性正变构调节剂（PAM）CIQ（+）增加了内在兴奋性，并增强了FSIN上NMDAR介导的EPSC。GluN 2C/D PAM的这种内在兴奋性的增加也在具有报告的FSIN低兴奋性的Dlx 5/6+/- FSIN发育缺陷模型中观察到。总之，这些数据表明GluN 2D PAM对FSIN的选择性调节，提供了一种对抗精神分裂症中FSIN缺陷的潜在机制。
Deficits in fast-spiking inhibitory interneurons (FSINs) within the dorsolateral prefrontal cortex (dlPFC) are hypothesized to underlie cognitive impairment associated with schizophrenia. Though representing a minority of interneurons, this key cell type coordinates broad neural network gamma-frequency oscillations, associated with cognition and cognitive flexibility. Here we report expression of GluN2D mRNA selectively in parvalbumin positive cells of human postmortem dlPFC tissue, but not pyramidal neurons, with little to no GluN2C expression in either cell type. In acute murine mPFC slices the GluN2C/D selective positive allosteric modulator (PAM), CIQ(+), increased the intrinsic excitability as well as enhanced NMDAR-mediated EPSCs onto FSINs. This increase in intrinsic excitability with GluN2C/D PAM was also observed in the Dlx 5/6+/- FSIN developmental deficit model with reported FSIN hypoexcitability. Together these data speak to selective modulation of FSINs by a GluN2D PAM, providing a potential mechanism to counter the FSIN-deficit seen in schizophrenia.