Department of Anatomy, Keio University School of Medicine, Shinjuku-ku Tokyo 160-8582, Japan.
J Neurosci. 2011 Oct 5;31(40):14116-25. doi: 10.1523/JNEUROSCI.2786-11.2011.
Phencyclidine (PCP) is a noncompetitive NMDA receptor antagonist, and it induces schizophreniform cognitive deficits in healthy humans and similar cognitive deficits in rodents. Although the PCP-induced cognitive deficits appear to be accompanied and possibly caused by dysfunction of GABAergic inhibitory interneurons in the prefrontal cortex (PFC), the potential benefit(s) of GABAergic interneuron manipulations on PCP-induced cognitive deficits remains unexplored. In this study we show that when embryonic medial ganglionic eminence (MGE) cells, many of which differentiate into cortical GABAergic interneurons in situ, were grafted into the medial PFC (mPFC) of neonatal mice, they differentiated into a specific class of GABAergic interneurons and became functionally integrated into the host neuronal circuitry in adults. Prior MGE cell transplantation into the mPFC significantly prevented the induction of cognitive and sensory-motor gating deficits by PCP. The preventive effects were not reproduced by either transplantation of cortical projection neuron precursors into the mPFC or transplantation of MGE cells into the occipital cortex. The preventive effects of MGE cell transplantation into the mPFC were accompanied by activation of callosal projection neurons in the mPFC. These findings suggest that increasing GABAergic interneuron precursors in the PFC may contribute to the development of a cell-based approach as a novel means of modulating the PFC neuronal circuitry and preventing schizophreniform cognitive deficits.
苯环利定（PCP）是一种非竞争性 NMDA 受体拮抗剂，它会在健康人群中引起精神分裂症样认知缺陷，并在啮齿动物中引起类似的认知缺陷。尽管 PCP 引起的认知缺陷似乎伴随着并可能由前额叶皮层（PFC）中 GABA 能抑制性中间神经元的功能障碍引起，但 GABA 能中间神经元操作对 PCP 引起的认知缺陷的潜在益处仍未得到探索。在这项研究中，我们表明，当胚胎内侧神经节隆起（MGE）细胞被移植到新生小鼠的内侧前额叶皮层（mPFC）中时，其中许多细胞会在原位分化为皮质 GABA 能中间神经元，它们分化为特定类型的 GABA 能中间神经元，并在成年后与宿主神经元回路功能整合。先前将 MGE 细胞移植到 mPFC 中可显著预防 PCP 引起的认知和感觉运动门控缺陷的诱导。将皮质投射神经元前体移植到 mPFC 中或将 MGE 细胞移植到枕叶皮质中均无法再现预防作用。将 MGE 细胞移植到 mPFC 中可预防认知缺陷，同时还伴随着 mPFC 中胼胝体投射神经元的激活。这些发现表明，增加 PFC 中的 GABA 能中间神经元前体可能有助于开发基于细胞的方法，作为调节 PFC 神经元回路和预防精神分裂症样认知缺陷的新方法。
