title: Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome.
abstract: Williams syndrome (WS), caused by microdeletion of some 21 genes on chromosome 7q11.23, is characterized by dysmorphic features, mental retardation or learning difficulties, elastin arteriopathy, and striking neurocognitive and social-behavioral abnormalities. Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (HF). Furthermore, deficits in spatial navigation and long-term memory, major cognitive domains dependent on hippocampal function, have been described in WS. We used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 participants with WS and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior HF in WS. Spectroscopic measures of N-acetyl aspartate, considered a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. These data demonstrate abnormalities in HF in WS in agreement with murine models, implicate LIMK1 and CYLN2 in human hippocampal function, and suggest that hippocampal dysfunction may contribute to neurocognitive abnormalities in WS.
authors.affiliation: Genes, Cognition, and Psychosis Program, National Institute of Mental Health, NIH, Department of Health and Human Services, Bethesda, MD 20892-1365, USA. andreasml@nih.gov
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Mervis
authors.forename: Deepak
authors.initials: D
authors.lastname: Sarpal
authors.forename: Paul
authors.initials: P
authors.lastname: Koch
authors.forename: Sonya
authors.initials: S
authors.lastname: Steele
authors.forename: Philip
authors.initials: P
authors.lastname: Kohn
authors.forename: Stefano
authors.initials: S
authors.lastname: Marenco
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Morris
authors.forename: Saumitra
authors.initials: S
authors.lastname: Das
authors.forename: Shane
authors.initials: S
authors.lastname: Kippenhan
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Mattay
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Karen Faith
authors.initials: KF
authors.lastname: Berman
mesh_terms: D000328:Adult; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005260:Female; D006624:Hippocampus / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D054461:Lim Kinases; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D010775:Photic Stimulation; D049268:Positron-Emission Tomography; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D018980:Williams Syndrome / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C109878:cytoplasmic linker protein 115; D001224:Aspartic Acid; C000179:N-acetylaspartate; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515893:Limk1 protein, mouse; D017346:Protein Serine-Threonine Kinases