BACKGROUND AND OBJECTIVE: Berberine, an isoquinoline alkaloid is reported to exhibit an anti-diabetic and antioxidant effect. Thus, this research study was conducted, for the first time, to evaluate the effect of berberine on synaptic plasticity at dentate gyrus (DG) of streptozotocin- induced diabetic rats.METHODS: In this study, the male Wistar rats (n=40) were randomly allocated into five groups: control, control berberine-treated (100 mg/kg), diabetic, berberine-treated diabetic (50, 100 mg/kg) groups. Diabetes was induced intraperinoneally administration at the dose of 55 mg/kg. Berberine was orally administered at doses of 50 and 100 mg/kg/day one week after STZ injection for a period of 7 weeks. Blood samples were taken from the tail vein 1, 3, 5, 7 weeks after STZ injection to measure blood glucose levels and Y maze task and passive avoidance test were used for assessment of learning and memory deficiency. Moreover electrophysiological evaluation including: field excitatory post-synaptic potentials (fEPSP) and Long-term potentiation (LTP) in perforate path-DG synapses was assessed in order to investigate the effect of berberine on synaptic plasticity. Field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude were also measured.FINDINGS: Increased blood glucose, reduced weight and short-term spatial memory in diabetic rats treated with berberine were improved (p<0.01). With respect to the control group (192±14), PS amplitude was significantly decreased in the diabetes group (112±12). In comparison to control group (112±12), chronic treatment with berberine (100 mg/kg) (192±10) improved PS amplitude (p<0.05). In addition fEPSP amplitude was significantly decreased in the diabetes group (121±6) in comparison to control group (167±11). In comparison to control group (152±6), chronic treatment with berberine (100 mg/kg) (147±3) improved fEPSP amplitude (p<0.05).CONCLUSION: This study showed that berberine treatment in dose dependent manner ameliorates memory impairment and improves synaptic plasticity in STZ diabetic rats.