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Activation of GABAB Receptors Ameliorates Cognitive Impairment via Restoring the Balance of HCN1/HCN2 Surface Expression in the Hippocampal CA1 Area in Rats With Chronic Cerebral Hypoperfusion

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Abstract

Hyperpolarization-activated cyclic-nucleotide-gated cation nonselective (HCN) channels are involved in the pathology of nervous system diseases. HCN channels and γ-aminobutyric acid (GABA) receptors can mutually co-regulate the function of neurons in many brain areas. However, little is known about the co-regulation of HCN channels and GABA receptors in the chronic ischemic rats with possible features of vascular dementia. Protein kinase A (PKA) and TPR containing Rab8b interacting protein (TRIP8b) can modulate GABAB receptors cell surface stability and HCN channel trafficking, respectively, and adaptor-associated kinase 1 (AAK1) inhibits the function of the major TRIP8b-interacting protein adaptor protein 2 (AP2) via phosphorylating the AP2 μ2 subunit. Until now, the role of these regulatory factors in chronic cerebral hypoperfusion is unclear. In the present study, we evaluated whether and how HCN channels and GABAB receptors were pathologically altered and investigated neuroprotective effects of GABAB receptors activation and cross-talk networks between GABAB receptors and HCN channels in the hippocampal CA1 area in chronic cerebral hypoperfusion rat model. We found that cerebral hypoperfusion for 5 weeks by permanent occlusion of bilateral common carotid arteries (two-vessel occlusion, 2VO) induced marked spatial and nonspatial learning and memory deficits, significant neuronal loss and decrease in dendritic spine density, impairment of long-term potentiation (LTP) at the Schaffer collateral-CA1 synapses, and reduction of surface expression of GABAB R1, GABAB R2, and HCN1, but increase in HCN2 surface expression. Meanwhile, the protein expression of TRIP8b (1a-4), TRIP8b (1b-2), and AAK1 was significantly decreased. Baclofen, a GABAB receptor agonist, markedly improved the memory impairment and alleviated neuronal damage. Besides, baclofen attenuated the decrease of surface expression of GABAB R1, GABAB R2, and HCN1, but downregulated HCN2 surface expression. Furthermore, baclofen could restore expression of AAK1 protein and significantly increase p-PKA, TRIP8b (1a-4), TRIP8b (1b-2), and p-AP2 μ2 expression. Those findings suggested that, under chronic cerebral hypoperfusion, activation of PKA could attenuate baclofen-induced decrease in surface expression of GABAB R1 and GABAB R2, and activation of GABAB receptors not only increased the expression of TRIP8b (1a-4) and TRIP8b (1b-2) but also regulated the function of TRIP8b via AAK1 and p-AP2 μ2, which restored the balance of HCN1/HCN2 surface expression in rat hippocampal CA1 area, and thus ameliorated cognitive impairment.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (NSFC, No. 81173038) to Lianjun Guo.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China

    Chang-jun Li, Yun Lu, Mei Zhou, Cai Li, Xu-lin Xu, Lian-jun Guo & Qing Lu

  2. Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Hubei Province, Wuhan, 430030, China

    Xu-lin Xu, Lian-jun Guo & Qing Lu

  3. Neurology Department, Huanggang central hospital, Hubei Province, Huanggang, 438000, People’s Republic of China

    Chang-jun Li

  4. Center for Integrated Protein Science (CIPSM) and Zentrum für Pharmaforschung, Department Pharmazie, Ludwig-Maximilians-Universität München, Munich, 80539, Germany

    Xian-gang Zong

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  1. Chang-jun Li
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Correspondence to Lian-jun Guo or Qing Lu.

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Chang-jun Li and Yun Lu contributed equally to this work.

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Li, Cj., Lu, Y., Zhou, M. et al. Activation of GABAB Receptors Ameliorates Cognitive Impairment via Restoring the Balance of HCN1/HCN2 Surface Expression in the Hippocampal CA1 Area in Rats With Chronic Cerebral Hypoperfusion. Mol Neurobiol 50, 704–720 (2014). https://doi.org/10.1007/s12035-014-8736-3

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