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.

Endosomal system genetics and autism spectrum disorders: A literature review

“…Its role in binding protein kinase A has been confirmed in platelet studies of haploinsufficient mice showing platelet dense granules, a phenomenon also seen in haploinsufficient autistic patients (Nuytens et al, 2013). Additionally, it has neuron specific expression, is necessary for dendritic morphology and synaptogenesis (Miller et al, 2015) and is associated with trans- golgi trafficking of intracellular, tubulovesicular endomembranes (Wang et al, 2000).…”

Enhanced long term potentiation and decreased AMPA receptor desensitization in the acute period following a single kainate induced early life seizure

“…Heterozygous mice for Dyt1, underlying DYT1 dystonia, display enhanced hippocampal LTP and motor deficits (Yokoi et al, 2015). Mice heterozygous for Neurobeachin, previously identified as an autism gene candidate, have enhanced CA1 LTP, altered self-grooming, social behaviors, contextual fear, and spatial learning and memory (Nuytens et al, 2013). Additionally, an adult rat model of depression showed a similar pattern of changes in LTP as seen in the KA-ELS rat after seizure, with no change in LTP 7 days, enhanced LTP 14 days, and impaired LTP 21 days following exposure to chronic unpredictable mild stress (Qiao et al, 2014).…”

Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder

“…Nair et al showed that Nbea -/- neurons have lower level of glutamate- and GABA receptors on their surface, and that these receptors accumulate at the post-Golgi site where Nbea would normally be located (Nair et al, 2013). In addition, NBEA has been linked to autism and autism symptoms (Castermans et al, 2003; Nuytens et al, 2013; Smith et al, 2002). …”