title: Dysregulation of presynaptic calcium and synaptic plasticity in a mouse model of 22q11 deletion syndrome.
abstract: The 22q11 deletion syndrome (22q11DS) is characterized by cognitive decline and increased risk of psychiatric disorders, mainly schizophrenia. The molecular mechanisms of neuronal dysfunction in cognitive symptoms of 22q11DS are poorly understood. Here, we report that a mouse model of 22q11DS, the Df(16)1/+ mouse, exhibits substantially enhanced short- and long-term synaptic plasticity at hippocampal CA3-CA1 synapses, which coincides with deficits in hippocampus-dependent spatial memory. These changes are evident in mature but not young animals. Electrophysiological, two-photon imaging and glutamate uncaging, and electron microscopic assays in acute brain slices showed that enhanced neurotransmitter release but not altered postsynaptic function or structure caused these changes. Enhanced neurotransmitter release in Df(16)1/+ mice coincided with altered calcium kinetics in CA3 presynaptic terminals and upregulated sarco(endo)plasmic reticulum calcium-ATPase type 2 (SERCA2). SERCA inhibitors rescued synaptic phenotypes of Df(16)1/+ mice. Thus, presynaptic SERCA2 upregulation may be a pathogenic event contributing to the cognitive symptoms of 22q11DS.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Laurie R
authors.initials: LR
authors.lastname: Earls
authors.forename: Ildar T
authors.initials: IT
authors.lastname: Bayazitov
authors.forename: Robert G
authors.initials: RG
authors.lastname: Fricke
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Berry
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Illingworth
authors.forename: Guy
authors.initials: G
authors.lastname: Mittleman
authors.forename: Stanislav S
authors.initials: SS
authors.lastname: Zakharenko
mesh_terms: D058165:22q11 Deletion Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics*; D017729:Presynaptic Terminals / Q000473:pathology* / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D002118:Calcium