title: Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory.
abstract: People with Down syndrome (DS) exhibit abnormal brain structure. Alterations affecting neurotransmission and signalling pathways that govern brain function are also evident. A large number of genes are simultaneously expressed at abnormal levels in DS; therefore, it is a challenge to determine which gene(s) contribute to specific abnormalities, and then identify the key molecular pathways involved. We generated RCAN1-TG mice to study the consequences of RCAN1 over-expression and investigate the contribution of RCAN1 to the brain phenotype of DS. RCAN1-TG mice exhibit structural brain abnormalities in those areas affected in DS. The volume and number of neurons within the hippocampus is reduced and this correlates with a defect in adult neurogenesis. The density of dendritic spines on RCAN1-TG hippocampal pyramidal neurons is also reduced. Deficits in hippocampal-dependent learning and short- and long-term memory are accompanied by a failure to maintain long-term potentiation (LTP) in hippocampal slices. In response to LTP induction, we observed diminished calcium transients and decreased phosphorylation of CaMKII and ERK1/2-proteins that are essential for the maintenance of LTP and formation of memory. Our data strongly suggest that RCAN1 plays an important role in normal brain development and function and its up-regulation likely contributes to the neural deficits associated with DS.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3168 Victoria, Australia.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Martin
authors.forename: Alicia
authors.initials: A
authors.lastname: Corlett
authors.forename: Daphne
authors.initials: D
authors.lastname: Dubach
authors.forename: Tomris
authors.initials: T
authors.lastname: Mustafa
authors.forename: Harold A
authors.initials: HA
authors.lastname: Coleman
authors.forename: Helena C
authors.initials: HC
authors.lastname: Parkington
authors.forename: Tobias D
authors.initials: TD
authors.lastname: Merson
authors.forename: James A
authors.initials: JA
authors.lastname: Bourne
authors.forename: Sílvia
authors.initials: S
authors.lastname: Porta
authors.forename: Maria L
authors.initials: ML
authors.lastname: Arbonés
authors.forename: David I
authors.initials: DI
authors.lastname: Finkelstein
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Pritchard
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D049229:Dendritic Spines; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D055724:Electrophysiological Phenomena; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology* / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D017774:Long-Term Potentiation; D008297:Male; D018782:Maze Learning; D057567:Memory, Long-Term; D008570:Memory, Short-Term; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000473:pathology
chemical_list: D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases