Chronic treatment with a MEK inhibitor reverses enhanced excitatory field potentials in Syngap1+/− mice

Maksym V. Kopanitsa, Gemma Gou, Nurudeen O. Afinowi, Àlex Bayés, Seth G.N. Grant, Noboru H. Komiyama

    Research output: Contribution to journalArticleResearchpeer-review

    3 Citations (Scopus)

    Abstract

    © 2018 Institute of Pharmacology, Polish Academy of Sciences Background: Synaptic Ras-GTPase-activating protein 1 (SYNGAP1) is an abundant brain-specific protein localized at the postsynaptic density of mammalian excitatory synapses. SYNGAP1 functions as a crucial regulator of downstream intracellular signaling triggered by N-methyl-D-aspartate receptor activation. One of the most important signaling pathways regulated by SYNGAP1 is the Ras-Raf-MEK-ERK pathway. SYNGAP1 deficiency is associated with hyperphosphorylation of MEK and ERK kinases and with altered synaptic function in Syngap1+/− mice. Loss-of-function mutations in the SYNGAP1 gene have been documented in many human cognitive and neurological disorders. However, there are currently no approaches that reverse the phenotypes of SYNGAP1 deficiency. Methods: Using electrophysiological recordings of field responses in hippocampal slices, we examined if disturbances of synaptic physiology in the hippocampus of 7–8-month old Syngap1+/− mice were sensitive to the effect of the MEK inhibitor PD-0325901 given orally for 6 days. Results: We found that in hippocampal slices from vehicle-treated Syngap1+/− mice, basal synaptic responses were higher and their long-term potentiation (LTP) was lower than in slices from wild-type littermates. Chronic administration of PD-0325901 normalized basal synaptic responses, but did not reverse LTP deficit. Conclusions: The differential sensitivity of basal synaptic transmission and LTP to MEK inhibition indicates that the effects of SYNGAP1 deficiency on these synaptic parameters are mediated by distinct pathways. Our findings also suggest that at least some physiological phenotypes of the germline Syngap1 mutation can be ameliorated by pharmacological treatment of adult animals.
    Original languageEnglish
    Pages (from-to)777-783
    JournalPharmacological Reports
    Volume70
    Issue number4
    DOIs
    Publication statusPublished - 1 Aug 2018

    Keywords

    • ERK
    • MEK
    • PD-0325901
    • SYNGAP1
    • Synaptic transmission

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