Abstract
Mitochondrial outer membrane permeability is conferred by a family of porin proteins. Mitochondrial porins conduct small molecules and constitute one component of the permeability transition pore that opens in response to apoptotic signals. Because mitochondrial porins have significant roles in diverse cellular processes including regulation of mitochondrial ATP and calcium flux, we sought to determine their importance in learning and synaptic plasticity in mice. We show that fear conditioning and spatial learning are disrupted in porin-deficient mice. Electrophysiological recordings of porin-deficient hippocampal slices reveal deficits in long and short term synaptic plasticity. Inhibition of the mitochondrial permeability transition pore by cyclosporin A in wild-type hippocampal slices reproduces the electrophysiological phenotype of porin-deficient mice. These results demonstrate a dynamic functional role for mitochondrial porins and the permeability transition pore in learning and synaptic plasticity.
Highlights
Porins, known as voltage-dependent anion channels (VDACs),1 are the most abundant proteins in the mitochondrial outer membrane [1]
We used a dose of cyclosporin 25-fold less in hippocampal slices to target cyclophilin D, which is very sensitive to cyclosporin A (CsA) (Ki ϭ 3.1–3.6 nM for CsA) [13], and our results are consistent with published studies of the effects of CsA on mitochondrial function
It is possible that the reduction in mitochondrial outer membrane permeability leads to developmental abnormalities in neuronal architecture, a pathological characterization of VDAC-deficient mice did not detect an anatomical defect despite the potential role of VDACs in apoptosis
Summary
Known as voltage-dependent anion channels (VDACs), are the most abundant proteins in the mitochondrial outer membrane [1]. They have highly conserved structural and electrophysiological characteristics across plant, yeast, mouse, and human species; mammals have three VDAC isoforms (VDAC1, VDAC2, and VDAC3) encoded by separate autosomal genes with the VDAC3 transcript undergoing alternative splicing in a tissue-specific manner [2, 3]. Participation of mitochondria in synaptic events depends on ion/metabolite flux through porins, the only known pores in the outer mitochondrial membrane. Using low doses of cyclosporin A and mice that lack the VDAC1 and/or the VDAC3 isoforms, we sought to determine the role of VDACs and the MPT in learning and synaptic plasticity
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