| Part Ⅰ Electrophysiological properties of hippocampal-corti-cal neural networks, role in the processes of learning and mem-ory in ratsObjective:To record hippocampal and cortical long-term potentiation (LTP) in rats in vivo, and describe changes in cellular mechanisms underlying synaptic plasticity. Methods:Recently, we introduced a method for the simultaneous recording of LTP in bilateral CA1regions and parietal association cortex (PtA), and observed differ-ences between Schaffer collateral-CA1pathway (SC), Schaffer collat-eral/associational commissural pathway (SAC) and Schaffer collateral/associational commissural-cortex pathway (SACC). Results:In this study, we found that (1) syn-aptic transmission of SAC and SACC pathways depended on hippocampal commis-sural fibers (dorsal and ventral hippocampal commissural fibers, the medial septum (MS) and hippocampal CA3commissural fibers),(2) nerve conduction velocity of SACC pathway might be higher than that of SAC pathway,(3) the input/output (I/O) curve of SC pathway was shifted to the left side, compared to that of SAC and SACC pathways,(4) all of three pathways could induce stable LTP, however, LTP of SAC and SACC pathways was much stronger than that of SC pathway,(5) the degree of paired-pulse facilitation (PPF) was weaker in SC pathway than that in SAC and SACC pathways,(6) after cutting off the corpus callosum and commissural fibers, the spatial learning and memory were impaired, and the ability to explore the novel envi-ronment and spontaneous locomotor activity were weakened. Conclusion:Our results suggested that hippocampal commissural fibers were very important for exchanging information between hemispheres, and basic differences in electrophysiological prop-erties of hippocampal-cortical neural networks play a vital role in the processes of learning and memory. Part II Clonidine suppresses the induction of long-term poten-tiation by inhibiting HCN channels at the Schaffer collateral-CA1synapse in anesthetized adult ratsObjective:Activation of alpha2-adrenoceptors inhibits long-term potentiation and long-term depression in many brain regions. However, effectiveness and mechanism of alpha2-adrenoceptors for synaptic plasticity at the Schaffer collateral-CA1syn-apses in rat in vivo is unclear. In the present study, we investigated the effects of al-phα2-adrenoceptors agonist clonidine on high frequency stimulation (HFS)-induced long-term potentiation (LTP) and paired-pulse facilitation (PPF) at the Schaffer col-lateral-CA1synapse of rat hippocampus in vivo. Methods:We have examined the effeets of clonidine, yohimbine and ZD7288on synaptic transmission LTP and PPF in the Schaffer collateral-CA1synapse in rat hippocampus in vivo. LTP and PPF were analyzed by extracellular electrophysiological recording. Results:Clonidine (0.05mg/kg,0.1mg/kg, ip) inhibited synaptic plasticity in a dose-dependently manner, ac-companying with the decreasing of aortic pressure and heart rate (HR) in anesthetized rats. Clonidine (1.25μg/kg,2.5μg/kg, icv,10min before HFS) also dose-dependently inhibited synaptic plasticity, which had no remarkable effect on HR and aortic pres-sure. However,20min after HFS, administration of clonidine (2.5μg/kg) had no ef-fect on LTP. The inhibitory effect of clonidine (2.5μg/kg) on LTP was completely re-versed by yohimbine (18μg/kg, icv) or ZD7288(5μg/kg, icv). Moreover, the inhibi-tion was accompanied by a significant increase of the normalized PPF ratio (PPR). Conclusion:Clonidine could suppress the induction of LTP at the Schaffer collateral-CA1synaps by inhibiting HCN channels. Part Ⅲ Activation of GABAB receptors ameliorates cognitive impairment via restoring the balance of HCN1/HCN2surface expression in the hippocampal CA1area in rats with chronic cerebral hypoperfusionObjective:Hyperpolarization-activated cyclic-nucleotide-gated cation non-selective (HCN) channels are involved in the pathology of nervous system diseases. HCN channels and y-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 hippocampal CA1area under the conditions of vascular dementia. In present study, we evaluated whether and how HCN channels and GABAB receptors were pathologically altered, and investi-gated neuroprotective effects of GABAB receptors activation and cross-talk networks between GABAB receptors and HCN channels in the hippocampal CA1area in chronic cerebral hypoperfusion rat model. Methods:SD rats were used and a2VO model was established. Four weeks after induction of hypoperfusion, the Morris water maze (MWM) was utilized to evaluate the spatial learning and memory performances of rats. One day after the Morris water maze test, novel object recognition (NOR) test evaluated non-spatial working memory. Five weeks after2VO, we recorded the field excitatory postsynaptic potential (fEPSP) and carried out biochemical studies (Im-munohistochemistry, anti-NeuN; Golgi silver staining, Spine density; Western blotting analysis, GABAB R1,GABAB R2, HCN1, HCN2, PKA, p-PKA, TRIP8b(1a-4), TRIP8b(lb-2), AAK1, p-AP2μ2). Results:We found that cerebral hypoperfusion for five weeks by permanent occlusion of bilateral common carotid arteries (2-vessel occlusion,2VO) induced marked spatial and non-spatial learning and mem-ory deficits, significant neuronal loss and decrease in dendritic spine density, impair-ment of long term potentiation (LTP) at the Schaffer collateral-CA1synapses, reduc- tion of surface expression of GABAB R1, GABAB R2and HCN1, but increase in HCN2surface expression. 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 R2possibly via activation of protein kinase A (PKA) under chronic cerebral hypoperfusion. Furthermore, ba-clofen could not only increase the expression of TPR containing Rab8b interacting protein (TRIP8b)(la-4) and TRIP8b (1b-2), but also regulate the function of TRIP8b via adaptor-associated kinase1(AAK1) and adaptor protein2μ2(AP2μ2), which restored the balance of HCN1/HCN2surface expression. Conclusion:Those findings suggested that activation of GABAB receptors ameliorated cognitive impair-ment via restoring the balance of HCN1/HCN2surface expression in the hippocam-pal CA1area in rats with chronic cerebral hypoperfusion. |
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