Differential role of NR2A and NR2B subunits in N-methyl-D-aspartate receptor antagonist-induced aberrant cortical gamma oscillations.
Differential role of NR2A and NR2B subunits in N-methyl-D-aspartate receptor antagonist-induced aberrant cortical gamma oscillations.
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DOI：
10.1016/j.biopsych.2011.10.002
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发表时间：
2012-06-01
影响因子：
10.6
通讯作者：
Kocsis, Bernat
中科院分区：
文献类型：
--
作者：
Kocsis, Bernat
NMDA受体（NMDA- r）功能障碍在精神分裂症认知功能障碍中起重要作用。NMDA-R拮抗剂在人类和啮齿动物中引发精神病症状和精神分裂症相关症状，包括皮质γ活动的强烈增加。NMDA-R由不同的亚基组成，越来越多的证据表明，NMDA-R拮抗剂引起的神经元损伤取决于它们对含有NR2A亚基的特定类型受体的作用。在人类精神分裂症患者中，NR2A在快速放电的中间神经元中选择性地减少。这些神经元对伽马振荡至关重要，表明伽马活动的病理变化可能取决于亚单位特异性NMDA-R缺陷。本研究验证了这一假设。记录自由运动大鼠的皮质脑电图，并在给药不同亚基选择性的NMDA-R拮抗剂后测量伽马功率的变化，这些拮抗剂包括nr2a偏好（PEAQX, n=5; NVP-AAM077, n=18）、nr2b选择性（伊芬普罗地尔，n=6；三-伊芬普罗地尔，n=4; Ro25-6985, n=13）、NR2C/ d选择性（PPDA, n=8）拮抗剂以及载体和非选择性NMDA-R拮抗剂（氯胺酮，n=10, MK801, n=12）。注射MK-801（n=6）、NVP-AAM077和Ro-6891 （n=5）后，检测脉冲前惊恐抑制的变化。非选择性NMDA-R拮抗剂和含有NR2A亚基的NMDA-R阻断可诱导伽马功率的强烈增加，同时发生门控缺陷和伽马振荡的低频调制减弱。相比之下，选择性阻断NR2B、C或D亚基受体的影响较小。NMDA-Rs在皮层伽马振荡中的主要亚型特异性差异可能对精神分裂症认知障碍的病理机制和治疗有影响。
NMDA receptor (NMDA-R) hypofunction plays an important role in cognitive impairment in schizophrenia. NMDA-R antagonists elicit psychotic symptoms in human and schizophrenia-relevant signs in rodents, including a strong increase in cortical gamma activity. NMDA-Rs are composed of different subunits and accumulating evidence indicates that neuronal damage due to NMDA-R antagonists depends on their action on a specific type of the receptor containing the NR2A subunit. In human schizophrenics, NR2A is selectively reduced in fast firing interneurons. These neurons are critical for gamma oscillations indicating that pathological changes in gamma activity may depend on subunit-specific NMDA-R deficit. The present study tested this hypothesis. Cortical electroencephalograms were recorded in freely moving rats and the changes in gamma power were measured after administration of NMDA-R antagonists with different subunit selectivity, including NR2A-preferring (PEAQX, n=5; NVP-AAM077, n=18), NR2B-selective (ifenprodil, n=6; threo-ifenprodil, n=4; Ro25–6985, n=13), and NR2C/D-selective (PPDA, n=8) antagonists, along with vehicle and non-selective NMDA-R antagonists (ketamine, n=10, MK801, n=12). Changes in prepulse inhibition of startle was tested after MK-801(n=6), NVP-AAM077, and Ro-6891 (n=5) injection. Strong increase in gamma power was induced by non-selective NMDA-R antagonists and by blockade of NMDA-Rs containing the NR2A subunit, with co-occurring gating deficits and diminished low frequency modulation of gamma oscillations. In contrast, selective blockade of NR2B, C, or D subunit-containing receptors had minor effects. Major subtype-specific differences in the role of NMDA-Rs in cortical gamma oscillation may have implications for the pathomechanism and treatment of cognitive impairment in schizophrenia.
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影响因子：
3.7
作者：
Hakami T;Jones NC;Tolmacheva EA;Gaudias J;Chaumont J;Salzberg M;O'Brien TJ;Pinault D
通讯作者：
Pinault D
影响因子：
3.3
作者：
Anastasio, N. C.;Xia, Y.;O'Connor, Z. R.;Johnson, K. M.
通讯作者：
Johnson, K. M.
影响因子：
64.8
作者：
Gielen, Marc;Retchless, Beth Siegler;Mony, Laetitia;Johnson, Jon W.;Paoletti, Pierre
通讯作者：
Paoletti, Pierre
影响因子：
56.9
作者：
Jentsch, JD;Redmond, DE;Roth, RH
通讯作者：
Roth, RH
影响因子：
2.5
作者：
Lakatos, P;Shah, AS;Schroeder, CE
通讯作者：
Schroeder, CE