Effects of the STriatal Enriched Tyrosine Phosphatase ( STEP ) Inhibitor TC ‐2153 on Hippocampal Long‐Term Depression and Synaptic Transmission: Paradoxical Effect on Phosphatase Activity and Role of Adenosine

Aims This study aimed to explore the effects of TC‐2153, the STriatal Enriched Tyrosine Phosphatase (STEP) inhibitor, on Long‐Term Depression (LTD) and basal synaptic transmission in hippocampal slices. Methods Extracellular field potentials were recorded in the CA1 area of the hippocampal slices. LTD was induced by low‐frequency stimulation and by metabotropic glutamate receptor stimulation. The activity of STEP was measured in hippocampal slices and in SH‐SY5Y cell culture by a colorimetric assay using p‐nitrophenol as a substrate. To evaluate adenosine levels, adenosine was extracted from hippocampal slices homogenates and measured by HPLC. Results TC‐2153 3 μM, applied to the slices one hour before and then along the electrophysiological recordings, blocked both forms of LTD. When hippocampal slices were treated with TC‐2153 for shorter periods, 10–20 min, TC‐2153 reduced synaptic transmission and increased STEP activity with an adenosine A1 receptor‐dependent mechanism. Consistently, we found that TC‐2153 increased adenosine levels in hippocampal slices. The increase in STEP activity after brief TC‐2153 treatment has been confirmed in SH‐SY5Y cells. Conclusion Our study confirms the role of STEP in LTD and reveals a new mechanism of action for TC‐2153. The unexpected adenosine‐dependent activation of STEP by TC‐2153 has significant implications for both basic research and potential therapeutic applications.