Figure 5

The mitochondrial permeability transition pore (mPTP) gain- or loss-of-function molecular manipulations rescue or mimic, respectively, the short-term potentiation (STP) phenotypes of Mrpl40^+/− mice. (a) Overexpression of Slc25a4 and GFP in the CA3 area of the hippocampus. (b) Mean augmentation measured in sham- or Slc25a4 OE-injected WT and Mrpl40^+/− mice. (c) Mean augmentation measured in control or Slc25a4 shRNA-injected WT and Mrpl40^+/− mice. The data are shown for three different Slc25a4 shRNAs (shRNA1, shRNA2, shRNA3) and are normalized to respective WT control levels. Numbers of neurons are shown inside columns. *P <0.05. (d) Model of mPTP-dependent mechanisms of STP dysfunction in 22q11DS. MRPL40 haploinsufficiency in 22q11DS reduces mitochondrial Ca²⁺ extrusion through impaired mPTP. This leads to a Ca²⁺ build-up in the mitochondrial matrix and enhanced Ca²⁺ transients in the mitochondrial matrix and cytosol during high-frequency activity, which in turn leads to enhanced synaptic vesicle release in presynaptic terminals. MCU, mitochondrial Ca²⁺ uniporter; NCX, Na⁺/Ca²⁺ exchanger; VDAC1, voltage-dependent anion channel 1; VGCC, voltage-gated calcium channels; WT, wild type. Upper traces represent cytosolic Ca²⁺ transients (GCaMP6), and lower traces represent mitochondrial Ca²⁺ transients (mitoGCaMP6).

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