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. Author manuscript; available in PMC: 2022 Jul 6.
Published in final edited form as: Sci Transl Med. 2021 Nov 3;13(618):eabd7695. doi: 10.1126/scitranslmed.abd7695

Figure 6 |. Mef2a/c overexpression improves cognition and rescues tauopathy-induced hyperexcitability in a mouse model of neurodegeneration.

Figure 6 |

A, Voltage-clamp recordings from pyramidal neurons in the medial prefrontal cortex (PS19+SH n = 20 cells from four animals; PS19+EE n = 15 cells from three animals; WT n = 9 cells from two animals) showed a rescue of hyperexcitability phenotypes after housing PS19 mice in EE conditions. Top: EE decreased hyperexcitability, as measured by number of action potentials in 500 ms for a given injecting current, (bottom, 2-way ANOVA for each pairwise comparison: WT vs. PS19 p-value = 0.0045, PS19 vs. PS19+EE p-value < 0.0001, WT vs. PS19+EE p-value = 0.0220). Bottom left: EE decreased membrane resistance of PS19 mice (independent t-test for each pairwise comparison: WT vs. PS19 p-value = 0.0050, PS19 vs. PS19+EE p-value = 0.0036, WT vs. PS19+EE p-value = 0.8173). Bottom right: EE reduced resting membrane potential of PS19 mice (independent t-test for each pairwise comparison: WT vs. PS19 p-value = 0.0163, PS19 vs. PS19+EE p-value < 0.0001, WT vs. PS19+EE p-value = 0.7077). B, Top: IHC from the medial prefrontal cortex of PS19 mice exposed to EE and SH conditions, staining for DAPI (blue), Rbfox3 (red), and Mef2a (green). Bottom: Imaris quantification of IHC with Mef2a/NeuN intensity plotted for individual nuclei across 3 EE and 3 SH mice. EE mice showed increased Mef2a intensity (unpaired t-test, p-value < 0.0001) compared to SH mice. C, Mef2a/c overexpression in 6-month-old PS19 mice enhances rates of fear extinction (n = 9 mice per group, unpaired t-test comparing % freezing post 2-shocks and % freezing on last day of extinction training, adj p=0.0057). D, Top: Voltage-clamp recordings from GFP-positive pyramidal neurons (OE n = 17 cells from 3 animals; Ctrl n = 10 cells from 3 animals) revealed that neurons overexpressing Mef2a and Mef2c (red) showed no difference in membrane input resistance (left) but an increased difference between baseline voltage and action potential threshold (right, unpaired t-test, p-value=0.0143), Bottom: Pyramidal neurons overexpressing Mef2a/c (identified by GFP fluorescence) exhibit reduced excitability as measured by voltage clamp recordings of number of action potentials fired in 500 ms after current injection (two-way ANOVA, p-value < 0.01 for group).