Transforming growth factor beta (TGF-beta) and Chloride channel-3 (CLC-3) are critical for inflammatory response, cellular proliferation and apoptosis in hippocampus neurons. However, the relationship between CLC-3 and TGF-beta/TGF-beta Receptor II (RII) pathway in diabetic encephalopathy (DE) is unknown. In this study, both diabetes rat model and diabetes cell model were employed to elucidate the mechanisms involved. The increased expressions of CLC-3 and TGF- beta RII with cognitive impairment were observed in diabetic rats. The most obvious reduction on the survival of HT22 cells was at 10 ng/ml or 15 ng/ml TGF- beta stimulation, while the expressions of CLC-3 and TGF-beta RII were significantly increased under high glucose condition. Moreover, the study showed that CLC-3 antagonists had no apparent effect on up-regulated TGF- beta RII, but TGF- beta 1 inhibitors could reduce the up-regulated CLC-3 under high glucose. Results from the present study indicated that CLC-3 and TGF- beta signals might be related to cognitive disorders. The CLC-3 might be modulated by TGF- beta /TGF- beta RII signaling pathway during the development of DE.