title: Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium.
abstract: Hemizygous deletion of a 1.5- to 3-megabase region on chromosome 22 causes 22q11.2 deletion syndrome (22q11DS), which constitutes one of the strongest genetic risks for schizophrenia. Mouse models of 22q11DS have abnormal short-term synaptic plasticity that contributes to working-memory deficiencies similar to those in schizophrenia. We screened mutant mice carrying hemizygous deletions of 22q11DS genes and identified haploinsufficiency of Mrpl40 (mitochondrial large ribosomal subunit protein 40) as a contributor to abnormal short-term potentiation (STP), a major form of short-term synaptic plasticity. Two-photon imaging of the genetically encoded fluorescent calcium indicator GCaMP6, expressed in presynaptic cytosol or mitochondria, showed that Mrpl40 haploinsufficiency deregulates STP via impaired calcium extrusion from the mitochondrial matrix through the mitochondrial permeability transition pore. This led to abnormally high cytosolic calcium transients in presynaptic terminals and deficient working memory but did not affect long-term spatial memory. Thus, we propose that mitochondrial calcium deregulation is a novel pathogenic mechanism of cognitive deficiencies in schizophrenia.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Devaraju
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Eddins
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Mellado-Lagarde
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Earls
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Westmoreland
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: G
authors.initials: G
authors.lastname: Quarato
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Zakharenko
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D057895:Haploinsufficiency; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D012261:Ribonucleoproteins; D012269:Ribosomal Proteins; D012559:Schizophrenia / Q000235:genetics
chemical_list: C485463:Mrpl40 protein, mouse; D009687:Nuclear Proteins; D012261:Ribonucleoproteins; D012269:Ribosomal Proteins; D002118:Calcium