title: Haploinsufficiency of the autism candidate gene Neurobeachin induces autism-like behaviors and affects cellular and molecular processes of synaptic plasticity in mice.
abstract: Neurobeachin (NBEA), a brain-enriched multidomain scaffolding protein involved in neurotransmitter release and synaptic functioning, has been identified as a candidate gene for autism spectrum disorder (ASD) in four unrelated patients haploinsufficient for NBEA. The aim of this study was to map the behavioral phenotype of Nbea(+/-) mice in order to understand its contribution to the pathogenesis of ASD. ASD-like behavioral variables of Nbea(+/-) mice were related to basal neuronal activity in different brain regions by in situ hybridizations and extracellular field recordings of synaptic plasticity in hippocampal cornu ammonis 1 (CA1) region. Levels of BDNF and phosphorylated cAMP response element-binding protein (CREB) were measured in an attempt to investigate putatively underlying changes in these neuromolecules. Nbea(+/-) mice exhibit several ASD-like features, including changes in self-grooming behavior, social behaviors, conditioned fear responses, and spatial learning and memory, which coincided with enhanced long-term potentiation (LTP) in their CA1 region. The observed alterations in learning and memory and hippocampal LTP are concomitant with decreased expression of the immediate early gene zif268 in dorsomedial striatum and hippocampal CA1 region, increased CREB phosphorylation, and increased hippocampal BDNF expression. These findings indicate that Nbea haploinsufficiency leads to various molecular and cellular changes that affect neuroplasticity and behavioral functions in mice, and could thus underlie the ASD symptomatology in NBEA deficient humans.
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: Nuytens
authors.forename: Ilse
authors.initials: I
authors.lastname: Gantois
authors.forename: Pieter
authors.initials: P
authors.lastname: Stijnen
authors.forename: Emilia
authors.initials: E
authors.lastname: Iscru
authors.forename: Annelies
authors.initials: A
authors.lastname: Laeremans
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Serneels
authors.forename: Lien
authors.initials: L
authors.lastname: Van Eylen
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Liebhaber
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.forename: Detlef
authors.initials: D
authors.lastname: Balschun
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Arckens
authors.forename: John W M
authors.initials: JW
authors.lastname: Creemers
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D007858:Learning / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics*; D010641:Phenotype; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C403265:Nbea protein, mouse; D009419:Nerve Tissue Proteins