Aim To investigate whether fluoxetine, a selective serotonin reuptake inhibitor(SSRI), could ameliorate cognitive impairments induced by chronic cerebral hypoperfusion in rats and to clarify the underlying mechanisms of its efficacy.Methods Rats were subjected to permanent bilateral occlusion of the common carotid arteries(twovessel occlusion, 2VO).Two weeks later, rats were treated with 30 mg · kg1 fluoxetine (intragastric injection, i.g.) for 6 weeks.Cognitive function was evaluated by Morris water maze (MWM) and novel objects recognition (NOR) test.Longterm potentiation (LTP) was used to address the underlying synaptic mechanisms.Western blot was used to quantify the protein levels.Results Fluoxetine treatment significantly improved the cognitive impairments caused by 2VO, accompanied with a reversion of 2VOinduced inhibitory of LTP.Furthermore, 2VO caused an upregulation of hyperpolarizationactivated cyclic nucleotidegated channel 2 (HCN2) surface expressions in the hippocampal CA1 area and fluoxetine also effectively recovered the upregulation of HCN2 surface expressions.Conclusion Fluoxetine can ameliorate cognitive impairments induced by chronic cerebral hypoperfusion and a possible mechanism may via downregulating HCN2 surface expression in the Hippocampal CA1 area.