c-Jun N-terminal kinase (JNK) signaling contributes to functional plasticity in the brain and cognition. Accumulating evidence implicates a role for MAP kinase kinase 7 (MAP2K7), a JNK activator encoded by the Map2k7 gene, and other JNK pathway components in schizophrenia (ScZ). Mice haploinsufficient for Map2k7 (Map2k7+/- mice) display ScZ-relevant cognitive deficits, although the mechanisms are unclear. Here we show that Map2k7+/- mice display translationally relevant alterations in brain function, including hippocampal and mesolimbic system hypermetabolism with a contrasting prefrontal cortex (PFC) hypometabolism, reminiscent of patients with ScZ. In addition Map2k7+/- mice show alterations in functional brain network connectivity paralleling those reported in early ScZ, including PFC and hippocampal hyperconnectivity and compromised mesolimbic system functional connectivity. We also show that although the cerebral metabolic response to ketamine is preserved, the response to dextroamphetamine (d-amphetamine) is significantly attenuated in Map2k7+/- mice, supporting monoamine neurotransmitter system dysfunction but not glutamate/NMDA receptor (NMDA-R) dysfunction as a consequence of Map2k7 haploinsufficiency. These effects are mirrored behaviorally with an attenuated impact of d-amphetamine on sensorimotor gating and locomotion, whereas similar deficits produced by ketamine are preserved, in Map2k7+/- mice. In addition, Map2k7+/- mice show a basal hyperactivity and sensorimotor gating deficit. Overall, these data suggest that Map2k7 modifies brain and monoamine neurotransmitter system function in a manner relevant to the positive and cognitive symptoms of ScZ.

中文翻译：

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Map2k7 Haploinsufficiency诱导与精神分裂症有关的脑成像内表型和行为表型。

c-Jun N末端激酶（JNK）信号传导有助于大脑的功能可塑性和认知能力。越来越多的证据表明，MAP激酶激酶7（MAP2K7），由Map2k7基因编码的JNK激活剂和精神分裂症（ScZ）中的其他JNK途径成分均起作用。尽管机理尚不清楚，但对于Map2k7（Map2k7 +/-小鼠）单倍不足的小鼠表现出与ScZ相关的认知缺陷。在这里，我们显示Map2k7 +/-小鼠在脑功能上显示翻译相关变化，包括海马和中脑边缘系统代谢亢进，而前额叶皮层（PFC）代谢相反，这使ScZ患者联想到。此外，Map2k7 +/-小鼠显示出与早期ScZ中报道的功能相似的功能性大脑网络连通性变化，包括PFC和海马超连通性以及中脑边缘系统功能受损。我们还显示，尽管保留了对氯胺酮的大脑代谢反应，但对Map2k7 +/-小鼠的右旋苯丙胺（d-苯丙胺）的反应明显减弱，支持单胺神经递质系统功能障碍，但不支持谷氨酸/ NMDA受体（NMDA-R）功能障碍Map2k7单体不足的后果。在Map2k7 +/-小鼠中，这些作用在行为上与d-苯异丙胺对感觉运动门控和运动的减弱影响相类似，而保留了由氯胺酮产生的类似缺陷。此外，Map2k7 +/-小鼠显示基础亢进和感觉运动门控缺陷。全面的，