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Anisomycin activates p38 MAP kinase to induce LTD in mouse primary visual cortex
Wei Xiong1, Ljubomir Z Kojic, Lanjing Zhang
1Brain Research Center, University of British Columbia, 2211 Wesbrook Mall, Brain Research Center, Vancouver, Canada BC V6T 2B5. weixiong@interchange.ubc.ca
Abstract:
Anisomycin is both a well-established protein synthesis inhibitor and a potent activator of the p38/JNK MAPK pathway. It has been used to block the late phase of long-term potentiation (LTP) and long-term depression (LTD) in hippocampus. In this study, we have found that anisomycin produces a time-dependent decline in the magnitude of the field EPSP (fEPSP) in acute brain slices of mouse primary visual cortex. This anisomycin-mediated fEPSP depression occludes NMDA receptor-dependent LTD induced by low-frequency stimulation (LFS). In contrast, two other protein synthesis inhibitors, emetine and cycloheximide, have no effect either on baseline synaptic transmission or on LTD. Moreover, the decline of the fEPSP caused by anisomycin can be rescued by the application of the p38 inhibitor SB203580 but not by the JNK inhibitor SP600125. These results indicate that activation of p38 MAPK by anisomycin induces LTD and subsequently occludes electrically induced LTD. Also, the occlusion of LFS-LTD by anisomycin suggests that common mechanisms may be shared between the two forms of synaptic depression. Consistent with this view, bath application of a membrane permeant peptide derived from the carboxyl tail of GluR2 subunit of AMPA receptor, which specifically blocks regulated AMPA receptor endocytosis, thereby preventing the expression of LFS-induced LTD, significantly reduced the anisomycin-induced decline of the fEPSP. In conclusion, our results indicate that anisomycin produces long-lasting depression of AMPA receptor-mediated synaptic transmission by activating p38 MAPK-mediated endocytosis of APMA receptors in mouse primary visual cortex.
Insights
Anisomycin triggers long-term depression (LTD) in the visual cortex by activating p38 MAPK, leading to AMPA receptor endocytosis. This process shares mechanisms with electrically induced LTD.
Area of Science:
- Neuroscience
- Synaptic Plasticity
- Molecular Biology
Background:
- Anisomycin is a known protein synthesis inhibitor and activator of p38/JNK MAPK pathways.
- It has been utilized to inhibit long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus.
Purpose of the Study:
- To investigate the effects of anisomycin on synaptic transmission in the mouse primary visual cortex.
- To determine the specific molecular pathways involved in anisomycin-induced synaptic depression.
- To explore the relationship between anisomycin-induced LTD and electrically induced LTD.
Main Methods:
- Acute brain slices from mouse primary visual cortex were used.
- Field excitatory postsynaptic potentials (fEPSPs) were recorded to measure synaptic transmission.
- Anisomycin, emetine, and cycloheximide were applied to assess their effects.
- Specific inhibitors (SB203580 for p38, SP600125 for JNK) were used.
- A peptide blocking AMPA receptor endocytosis was applied.
Main Results:
- Anisomycin caused a time-dependent decrease in fEPSP magnitude in the visual cortex.
- This anisomycin-induced depression occluded NMDA receptor-dependent LTD induced by low-frequency stimulation (LFS).
- p38 MAPK inhibition (SB203580) rescued the anisomycin effect, while JNK inhibition (SP600125) did not.
- Blocking AMPA receptor endocytosis reduced the anisomycin-induced fEPSP decline.
Conclusions:
- Anisomycin induces long-term depression (LTD) in the mouse visual cortex via p38 MAPK activation.
- This p38 MAPK pathway activation leads to AMPA receptor endocytosis, causing synaptic depression.
- The findings suggest shared molecular mechanisms between anisomycin-induced LTD and electrically induced LTD.
